Down Syndrome

A number sign (#) is used with this entry because the disorder is caused by a chromosomal aberration, trisomy 21, and many genes are involved in the phenotype.

In particular, transient myeloproliferative disorder and megakaryoblastic leukemia of Down syndrome are associated with mutations in the GATA1 gene (305371) in conjunction with trisomy 21. Somatic mutations in the JAK2 gene (147796) are associated with acute lymphoblastic leukemia (ALL; 613065) in patients with Down syndrome.

Down syndrome, the most frequent form of mental retardation caused by a microscopically demonstrable chromosomal aberration, is characterized by well-defined and distinctive phenotypic features and natural history. It is caused by triplicate state (trisomy) of all or a critical portion of chromosome 21.

Down syndrome (Down, 1866), a particular combination of phenotypic features that includes mental retardation and characteristic facies, is caused by trisomy 21 (Lejeune et al., 1959), one of the most common chromosomal abnormalities in liveborn children.

It has long been recognized that the risk of having a child with trisomy 21 increases with maternal age (Penrose, 1933). For example, the risk of having a liveborn with Down syndrome at maternal age 30 is 1 in 1,000 and at maternal age 40 is 9 in 1,000 (Hook, 1982; Hook et al., 1983).

Individuals with Down syndrome often have specific major congenital malformations such as those of the heart (30-40% in some studies), particularly atrioventricular septal defect (AVSD), and of the gastrointestinal tract, such as duodenal stenosis or atresia, imperforate anus, and Hirschsprung disease (142623). Some of these clinical features have been incorporated into the preliminary phenotypic maps of chromosome 21 developed by Korenberg (1993), Korenberg et al. (1992), and Delabar et al. (1993).

Leukemia (both ALL and AML) and leukemoid reactions show increased incidence in Down syndrome (Fong and Brodeur, 1987; Robinson, 1992). Estimates of the relative risk have ranged from 10 to 20 times higher than the normal population; in particular, acute megakaryocytic leukemia occurs 200 to 400 times more frequently in the Down syndrome than in the chromosomally normal population (Zipursky et al., 1987). Transient leukemoid reactions have been reported repeatedly in the neonatal period, and this phenotype has been tentatively mapped to the proximal long arm of chromosome 21 (Niikawa et al., 1991).

Ninety percent of all Down syndrome patients have a significant hearing loss, usually of the conductive type (Mazzoni et al., 1994).

For additional defects and phenotypic characteristics, see Epstein (1989).

Patients with Down syndrome develop the neuropathologic hallmarks of Alzheimer disease at a much earlier age than individuals with Alzheimer disease without trisomy 21 (Wisniewski et al., 1985). Characteristic senile plaques and neurofibrillary tangles are present in the brain of all individuals with Down syndrome over the age of 40 years (Wisniewski et al., 1985). The triplication of the amyloid precursor protein gene (APP; 104760) may be the cause of this phenomenon. Several mutations in the APP gene have been described in families with early-onset Alzheimer disease without trisomy 21 (e.g., Goate et al., 1991).

Castilla et al. (1998) performed an epidemiologic analysis of the association of polydactyly with other congenital anomalies in 5,927 consecutively born polydactyly cases. Trisomy 13, Meckel syndrome (249000), and Down syndrome explained 255 of the 338 syndromic polydactyly cases. Down syndrome was strongly associated with first-digit duplication, and negatively associated with postaxial polydactyly.

In a retrospective study of high-altitude pulmonary edema performed at Children's Hospital in Denver, Durmowicz (2001) identified 6 of 52 patients as having Down syndrome. Five of the 6 children had preexisting illnesses including chronic pulmonary hypertension, existing cardiac defects with left-to-right shunt, or previous defects of left-to-right shunt that had been repaired. One child had Eisenmenger syndrome. Durmowicz (2001) suggested caution in traveling to even moderate altitudes with children with Down syndrome.

To determine whether newborns with DS have decreased blood T4 (thyroxine; tetraiodothyronine) concentrations at the time of the neonatal screening, van Trotsenburg et al. (2003) conducted an observational study in a large and representative cohort of Dutch children with DS born in 1996 and 1997. Results of congenital hypothyroidism (CH) screening measuring T4, TSH (see 188540), and T4-binding globulin (314200) concentrations were analyzed in comparison with clinical information obtained by interviewing the parents and data from the general newborn population and a large control group. The mean T4 concentration of the 284 studied children with DS was significantly decreased. The individual T4 concentrations were normally (Gaussian) distributed but shifted to lower concentrations. Mean TSH and T4-binding globulin concentrations were significantly increased and normal, respectively. The decreased T4 concentration, left-shifted normal distribution, and mildly elevated TSH concentrations pointed to a mild hypothyroid state in newborns with DS and supported the existence of a DS-specific thyroid (regulation) disorder.

In a case-control study, Tyler et al. (2004) found that the rate of symptomatic gallbladder disease was 25% among 28 index cases of adults with Down syndrome compared to 4.5% among sex-matched controls (p = 0.002). The adjusted relative risk for gallbladder disease among individuals with Down syndrome was 3.52.

Henry et al. (2007) examined complete blood counts obtained in the first week of life from 158 consecutive neonates with Down syndrome and found that neutrophilia, thrombocytopenia, and polycythemia were the most common hematologic abnormalities, occurring in 80%, 66%, and 33% of patients, respectively.

Survival

Zhu et al. (2013) studied survival among individuals with Down syndrome from the Danish population using a national cohort of 3,530 persons with Down syndrome identified from the Danish Cytogenetic Register and a reference cohort of persons without Down syndrome randomly selected from the general population followed from 1 April 1968 to 15 January 2009 by linkages to the Register of Causes of Death and the Civil Registration System. Overall, persons with Down syndrome had higher mortality than the reference cohort but to a lesser degree for persons with mosaic trisomy 21 than for persons with standard trisomy 21 or with Robertsonian translocations (hazard ratio 4.98 (95% CI 3.52-7.08), 8.94 (8.32-9.60) and 10.23 (7.50-13.97), respectively). Among persons with Down syndrome born after April 1968, more recent birth cohorts had lower mortality rates than older birth cohorts, which was largely due to declining mortality among persons with Down syndrome who also had congenital heart defects.

During the second trimester of pregnancy, serum alpha-feto protein (AFP; 104150) is commonly used for evaluating the risk of Down syndrome. Decreased levels of AFP are indicative of Down syndrome. However, Petit et al. (2009) noted that a congenital deficiency of AFP may result in decreased AFP in the maternal serum and amniotic fluid. They reported a male fetus with congenital absence of AFP, due to a truncating mutation (104150.0003), who showed normal growth and development.

Tsui et al. (2010) showed that analysis of PLAC4 (613770) can aid in the noninvasive prenatal detection of trisomy 21 using maternal plasma samples. PLAC4 is transcribed from chromosome 21 in the placenta and is specific for the fetus in maternal plasma. One analytic method, termed the RNA-SNP approach, measures the ratio of alleles for a SNP in placenta-derived mRNA molecules in maternal plasma. The RNA-SNP approach detected the deviated RNA-SNP allelic ratio in PLAC4 mRNA caused by an imbalance in chromosome 21 dosage. In a study of 153 pregnant women, the diagnostic sensitivity and specificity using this method was 100% and 89.7%, respectively. In fetuses homozygous for the SNP, a second analytic approach was used, which quantifies circulating PLAC4 mRNA concentrations. Trisomy 21 pregnancies showed significantly increased plasma PLAC mRNA compared to unaffected pregnancies. The sensitivity and specificity of this method were 91.7% and 81.0% using real-time PCR, and 83.3% and 83.5% using digital PCR. The overall findings suggested that the synergistic use of these 2 methods will increase the yield of correct diagnosis of trisomy 21 using noninvasive methods.

Most individuals (95%) with trisomy 21 have 3 free copies of chromosome 21; in about 5% of patients, 1 copy is translocated to another acrocentric chromosome, most often chromosome 14 or 21 (Thuline and Pueschel, 1982; Hook, 1982). In 2 to 4% of cases with free trisomy 21 there is recognizable mosaicism for a trisomic and a normal cell line (Mikkelsen, 1977).

Origin of Free Trisomy 21

The availability of highly informative DNA markers has allowed the parental origin of the extra chromosome 21 and the meiotic/mitotic origin to be determined. More than 400 families have been studied (Antonarakis et al. (1991, 1992); Antonarakis, 1993; Sherman et al. (1991, 1992)) and the results are as follows: (1) Errors in meiosis that lead to trisomy 21 are overwhelmingly of maternal origin; only about 5% occur during spermatogenesis. (2) Most errors in maternal meiosis occur in meiosis I and the mean maternal age associated with these is 32 years (the mean maternal age of the general population is approximately 27 years). Thus, meiosis I errors account for 76 to 80% of maternal meiotic errors and 67 to 73% of all instances of free trisomy 21. (3) Maternal meiosis II errors constitute 20 to 24% of maternal errors and 18 to 20% of all cases of free trisomy 21. The mean maternal age is also advanced and is 31.4 in one study and 34.1 in another. (4) In rare families in which there is paternal nondisjunction, most of the errors occur in meiosis II. The mean maternal and paternal ages are similar to the mean reproductive age in western societies. (5) In 5% of trisomic individuals the supernumerary chromosome 21 appears to result from an error in mitosis. In these cases there is no advanced maternal age and there is no preference for which chromosome 21 is duplicated in the mitotic error.

Warren et al. (1987) and Sherman et al. (1991) have described an association between trisomy 21 and reduced recombination in meioses. A significant proportion (at least 30%) of maternal meiosis I nondisjunctions of chromosome 21 is associated with failure to recombine. It is not known whether the paucity of recombination is related to maternal age; moreover, the mechanism of recombination failure (asynapsis vs abnormalities during or after synapsis) is as yet unclear.

There is a well-established association between altered recombination patterns and nondisjunction of human chromosomes. Brown et al. (2000) investigated the possibility of reduced recombination in the total genome of an egg with a nondisjoined chromosome 21 and no detectable recombination. By genotyping 15 patients (at 366 autosomal markers) with trisomy 21, as well as their parents and maternal grandparents, the authors found a statistically significant genomewide reduction (p less than 0.05) in the mean recombination rate in these eggs with nondisjoined chromosomes 21. This reduction was felt to be consistent with normal variation in recombination observed among eggs. The authors hypothesized that when the number of genomewide recombination events is less than some threshold, specific chromosomes may be at an increased risk for nondisjunction.

Origin of Translocation Trisomy 21

All de novo t(14;21) trisomies studied have originated in maternal germ cells (Petersen et al., 1991; Shaffer et al., 1992). The mean maternal age was 29.2 years. In de novo t(21;21) Down syndrome the situation is different (Grasso et al., 1989; Antonarakis et al., 1990; Shaffer et al., 1992). In most cases (14 out of 17) the t(21;21) is an isochromosome (dup21q) rather than the result of a Robertsonian translocation caused by a fusion between 2 heterologous chromatids. About half were of paternal and half of maternal origin. In the 3 de novo t(21;21) true Robertsonian trisomy 21 cases, the extra chromosome 21 was maternal.

Down Syndrome Critical Region

Mapping of the chromosomal region that, if triplicated, results in the phenotypic characteristics of Down syndrome has been facilitated by the use of DNA samples from individuals who have partial trisomy 21 with or without features of the Down syndrome phenotype (Rahmani et al., 1989; McCormick et al., 1989; Korenberg et al., 1990; Delabar et al., 1993; Korenberg, 1993). Although detailed analysis of these DNAs is still under way, an area of approximately 5 Mb between loci D21S58 and D21S42 has been identified that is associated with mental retardation and most of the facial features of the syndrome. In particular, a subregion that includes D21S55 and MX1 (interferon-induced protein p78; 147150), the latter being located in band 21q22.3, has been associated with mental retardation and several morphologic features, including oblique eye fissure, epicanthus, flat nasal bridge, protruding tongue, short broad hands, clinodactyly of the fifth finger, gap between first and second toes, hypotonia, short stature, Brushfield spots, and characteristic dermatoglyphics (Delabar et al., 1993). Additional phenotypic characteristics may map outside the minimum critical region (symbolized DCR). Material from other rare patients who have features of Down syndrome but no visible chromosomal abnormality may help to narrow down the critical region. In several such studies, however, no triplicated region has been identified (McCormick et al., 1989; Delabar et al., 1993). It is possible that these patients do not have any chromosome 21 abnormality and their phenotype is a phenocopy of Down syndrome.

Korenberg et al. (1990) defined the critical region for AVSD as involving D21S39, D21S42, and D21S43. Their subsequent publications further refined the minimum region for the major phenotypic features, although it remains unclear whether the region essential for AVSD is the same, since many clinical reports give insufficient information about the nature of the heart defect (Korenberg et al., 1992). Korenberg et al. (1992) correlated the human and mouse chromosome maps and suggested that the area of greatest interest extends from D21S55 to MX1.

By analysis of a 3-generation Japanese family containing 4 Down syndrome individuals with partial trisomy 21 (Korenberg et al., 1990), Ohira et al. (1996) defined a 1.6-Mb region between LA68 and ERG (165080) in 21q22 as the Down syndrome critical region. They constructed a contig map covering more than 95% of this 1.6-Mb region.

Genes Within the Down Syndrome Critical Region

Fuentes et al. (1995) cloned a gene (RCAN1; 602917), which they designated DSCR1, from the Down syndrome critical region that is highly expressed in brain and heart, and suggested it as a candidate for involvement in the pathogenesis of DS, in particular mental retardation and/or cardiac defects.

Nakamura et al. (1997) identified DSCR4 (604829) as 2 ESTs that map to the 1.6-Mb Down syndrome critical region. DSCR4 is predominantly expressed in placenta.

Vidal-Taboada et al. (1998) identified DSCR2 (605296) within the Down syndrome critical region 2 between DNA marker D21S55 and MX1.

Nakamura et al. (1997) identified DSCR3 (605298) within the Down syndrome critical region.

Using indexing-based differential display PCR on neuronal precursor cells to study gene expression in Down syndrome, Bahn et al. (2002) found that genes regulated by the REST (600571) transcription factor were selectively repressed. One of these genes, SCG10 (600621), which encodes a neuron-specific growth-associated protein, was almost undetectable. The REST factor itself was also downregulated by 49% compared to controls. In cell culture, the Down syndrome cells showed a reduction of neurogenesis, as well as decreased neurite length and abnormal changes in neuron morphology. The authors noted that REST-regulated genes play an important part in brain development, plasticity, and synapse formation, and they suggested a link between dysregulation of REST and some of the neurologic deficits seen in Down syndrome.

Eggermann et al. (2010) reported a patient with a paternally inherited 0.46-Mb duplication of chromosome 21q22, including the KCNE1 (176261) and RCAN1 genes, who did not have typical facial or cardiac features of Down syndrome. The patient had a clinical phenotype resembling Silver-Russell syndrome (SRS; 180860), which is characterized by poor growth, but typical epigenetic changes associated with SRS were excluded. The duplication was inherited from the unaffected father. Eggermann et al. (2010) concluded that the RCAN1 gene is not sufficient for generating the phenotypic features associated with Down syndrome.

Acute Megakaryoblastic Leukemia of Down Syndrome

Children with Down syndrome have a 10- to 20-fold elevated risk of developing leukemia, particularly acute megakaryoblastic leukemia (AMKL). Wechsler et al. (2002) showed that leukemic cells from individuals with Down syndrome-related AMKL had mutations in the GATA1 gene (305371).

Look (2002) reviewed the mechanism by which GATA1 mutations might interact with trisomy 21 to result in AMKL. He pointed out that several lines of evidence indicated that at least 2 classes of mutations are needed to transform a normal hematopoietic stem cell into a clonal acute myeloid leukemia. One class imparts a myeloproliferative or survival advantage, as illustrated by activating mutations in FLT3 (136351), encoding a receptor tyrosine kinase, or the increased dosage of genes in chromosome 21 in persons with Down syndrome. To generate overt leukemia, a second class of genetic alterations must produce lineage-specific blocks in differentiation. The mutations responsible for this step have been demonstrated mainly in genes encoding chimeric transcription factors produced by chromosomal translocation. GATA1 is a transcription factor that plays a pivotal role in myeloid lineage commitment.

Transient Myeloproliferative Disorder of Down Syndrome

As many as 10% of infants with Down syndrome present with transient myeloproliferative disorder (TMD) at or shortly after birth. TMD is characterized by an abundance of blasts within peripheral blood and liver, and undergoes spontaneous remission in a majority of cases. TMD may be a precursor to AMKL, with an estimated 30% of TMD patients developing AMKL within 3 years. Mutations in GATA1 are associated with AMKL of Down syndrome. To determine whether the acquisition of GATA1 mutations is a late event restricted to acute leukemia, Mundschau et al. (2003) analyzed GATA1 in DNA from TMD patients. They found that GATA1 was mutated in the TMD blasts from every infant examined. These results demonstrated that GATA1 is likely to play a critical role in the etiology of TMD, and mutagenesis of GATA1 represents a very early event in myeloid leukemogenesis in Down syndrome. Hitzler et al. (2003) likewise presented evidence that GATA1 mutations are an early event, and that AMKL arises from latent transient leukemia clones following initial apparent remission. All 7 patients reported by Mundschau et al. (2003) and almost all of the patients studied by Hitzler et al. (2003) had deletions or insertions in the GATA1 gene rather than nucleotide substitutions.

Taketani et al. (2002) screened the RUNX1 gene (151385) in 46 Down syndrome patients with hematologic malignancies. They identified a heterozygous missense mutation (H58N; 151385.0008) in 1 patient diagnosed with TMD 5 days after birth. The patient died suddenly 12 months after birth; it was not known whether she developed acute myeloid leukemia.

Atrioventricular Septal Defects of Down Syndrome

Given that mutations in the CRELD1 gene (607170) appear to be a risk factor for atrioventricular septal defect (AVSD) in the euploid population, and the fact that trisomy 21 is by far the most common finding associated with AVSD, Maslen et al. (2006) analyzed the CRELD1 gene in 39 individuals with Down syndrome and complete AVSD. They identified heterozygosity for missense mutations in 2 infants (607170.0001 and 607170.0005, respectively), and suggested that defects in CRELD1 may contribute to the pathogenesis of AVSD in the context of trisomy 21.

Ackerman et al. (2012) used a candidate gene approach among individuals with Down syndrome and complete AVSD (141 cases) and Down syndrome with no congenital heart defect (141 controls) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. Ackerman et al. (2012) found a significant excess (p less than 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, they found potentially damaging variants in nearly 20% of cases but fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in 6 genes: COL6A1 (120220), COL6A2 (120240), CRELD1 (mutations in which have already been identified as a cause of AVSD; see 606217), FBLN2 (135821), FRZB (605083), and GATA5 (611496). Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGFA (192240) pathway, suggesting to Ackerman et al. (2012) that rare variants in this pathway might contribute to the genetic underpinnings of AVSD in humans.

Acute Lymphoblastic Leukemia of Down Syndrome

Bercovich et al. (2008) identified somatic mutations in the JAK2 gene (147796) in 16 (18%) of 88 patients with Down syndrome-associated acute lymphoblastic leukemia. Only 1 of 109 patients with non-Down syndrome-associated leukemia had the mutation, but this child was also found to have an isochromosome 21q. All the JAK2-associated leukemias were of the B-cell precursor type. Children with a JAK2 mutation were younger (mean age 4.5 years) compared to patients without JAK2 mutations (8.6 years) at diagnosis. Five mutant JAK2 alleles were identified, each affecting a highly conserved residue: arg683 (i.e., R683G, R683S, R683K). In vitro functional expression studies in mouse hematopoietic progenitor cells showed that the mutations caused constitutive Jak/Stat activation and cytokine-independent growth, consistent with a gain of function. This growth was sensitive to pharmacologic inhibition with a JAK inhibitor. Modeling studies showed that arg683 is located in an exposed conserved region of the JAK2 pseudokinase domain in a region different from that implicated in myeloproliferative disorders. Bercovich et al. (2008) concluded that there is a specific association between constitutional trisomy 21 and arg683 JAK2 mutations that predispose to the development of B-cell ALL in patients with Down syndrome.

Lyle et al. (2009) used array comparative genomic hybridization to analyze 30 patients with anomalies of chromosome 21, including 19 with partial trisomy 21 and 11 with partial monosomy 21, all for different segments of the chromosome. They also examined the phenotypes of 5 patients with a Down syndrome-like phenotype with a normal karyotype and 6 with complete trisomy 21. The majority of the phenotypes mapped to distal 21; averaging the phenotype score indicated a region approximately 37 to 44 Mb, which was involved in most Down syndrome phenotypes. These results were not surprising, as this is the most gene-rich region of chromosome 21. Five patients were trisomic for proximal 21 and did not include the so-called Down syndrome critical region (DSCR), thus excluding the possibility there is a single DSCR responsible for all aspects of the phenotype.

The frequency of trisomy 21 in the population is 1 in 650 to 1,000 live births (Hook, 1982).

As a first step in identifying the genes responsible for individual features of Down syndrome and their pathophysiology, Korenberg et al. (1994) established a panel of cell lines derived from 16 individuals with Down syndrome caused by duplication of small regions of chromosome 21. The molecular breakpoints were determined using fluorescence in situ hybridization and Southern blot dosage analysis of 32 markers unique to chromosome 21. Combining this information with detailed clinical evaluations of the subjects, Korenberg et al. (1994) constructed a 'phenotypic map' that included 25 features and assigned regions of 2 to 20 Mb as likely to contain the genes responsible. This study provided evidence for a significant contribution of genes outside the D21S55 region to the DS phenotypes, including the facies, microcephaly, short stature, hypotonia, abnormal dermatoglyphics, and mental retardation. The results strongly suggest that DS is a contiguous gene syndrome and make it unlikely that a single DS chromosomal region is responsible for most of the DS phenotypic features.

Busciglio et al. (2002) found that astrocyte and neuronal cell cultures derived from Down syndrome fetal brains had increased intracellular levels of insoluble beta-amyloid-42 and decreased levels of secreted beta-amyloid. These abnormal patterns of APP (104760) processing were recapitulated in normal astrocytes by inhibition of mitochondrial metabolism. In addition, DS astrocytes showed impaired mitochondrial metabolism. Busciglio et al. (2002) postulated that mitochondrial dysfunction in Down syndrome may lead to intracellular deposition of beta-amyloid and increased neuronal vulnerability.

Arron et al. (2006) reported that 2 genes, DSCR1 (RCAN1; 602917) and DYRK1A (600855), that lie within the critical region of human chromosome 21 act synergistically to prevent nuclear occupancy of NFATc transcription factors (see 600489), which are regulators of vertebrate development. Arron et al. (2006) used mathematical modeling to predict that autoregulation within the pathway accentuates the effects of trisomy of DSCR1 and DYRK1A, leading to failure to activate NFATc target genes under specific conditions. The authors' observations of calcineurin (see 114105)- and Nfatc-deficient mice, Dscr1- and Dyrk1a-overexpressing mice, mouse models of Down syndrome, and human trisomy 21 are consistent with these predictions. Arron et al. (2006) suggested that the 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down syndrome. Arron et al. (2006) concluded that more generally, their observations suggest that the destabilization of regulatory circuits can underlie human disease.

In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free calcium ion levels, they are dephosphorylated by the calmodulin (114180)-dependent phosphatase calcineurin and translocate to the nucleus. NFAT dephosphorylation by calcineurin is countered by distinct NFAT kinases, among them casein kinase-1 (CK1; 600505), and glycogen synthase kinase-3 (GSK3; see 605004). Gwack et al. (2006) used a genomewide RNA interference screen in Drosophila to identify additional regulators of the signaling pathway leading from calcium ion-calcineurin to NFAT. This screen was successful because the pathways regulating NFAT subcellular localization (calcium ion influx, calcium ion-calmodulin-calcineurin signaling, and NFAT kinases) are conserved across species, even though calcium ion-regulated NFAT proteins are not themselves represented in invertebrates. Using the screen, Gwack et al. (2006) identified DYRKs (dual-specificity tyrosine phosphorylation-regulated kinases) as novel regulators of NFAT. DYRK1A and DYRK2 (603496) counter calcineurin-mediated dephosphorylation of NFAT1 by directly phosphorylating the conserved serine-proline repeat 3 (SP3) motif of the NFAT regulatory domain, thus priming further phosphorylation of the SP2 and serine-rich region 1 (SRR1) motifs by GSK3 and CK1, respectively. Thus, Gwack et al. (2006) concluded that genetic screening in Drosophila can be successfully applied to cross evolutionary boundaries and identify new regulators of a transcription factor that is expressed only in vertebrates.

Down syndrome is characterized by extensive phenotypic variability; while cognitive impairment, muscle hypotonia at birth, and dysmorphic features occur to some extent in all affected individuals, most associated traits occur in only a fraction of affected individuals. Since Down syndrome is caused by genomic dosage imbalance, Prandini et al. (2007) hypothesized that variation in expression of genes on chromosome 21 in individuals with Down syndrome influences the phenotypic variability among affected individuals. They studied gene expression variation in 14 lymphoblastoid and 17 fibroblast cell lines from individuals with Down syndrome and an equal number of controls. Gene expression was assayed on 100 and 106 chromosome 21 genes and 23 and 26 non-chromosome 21 genes in lymphoblastoid and fibroblast cell lines, respectively. Surprisingly, only 39% and 62% of chromosome 21 genes in lymphoblastoid and fibroblast cells, respectively, showed a statistically significant difference between Down syndrome and normal samples, although the average upregulation of chromosome 21 genes was close to the expected 1.5-fold in both cell types. According to the degree of overlapping expression levels, Prandini et al. (2007) classified all genes into 3 groups: (A) nonoverlapping, (B) partially overlapping, and (C) extensively overlapping expression distributions between normal and Down syndrome samples. The authors hypothesized that, in each cell type, group A genes are the most dosage-sensitive and are most likely involved in the constant Down syndrome traits; group B genes may be involved in variable Down syndrome traits; and group C genes are not dosage-sensitive and are least likely to participate in Down syndrome pathologic phenotypes.

Using a transchromosomic mouse model of Down syndrome, Canzonetta et al. (2008) showed that a 30 to 60% reduced expression of NRSF/REST (600571), a key regulator of pluripotency and neuronal differentiation, is an alteration that persists in trisomy 21 from undifferentiated embryonic stem cells to adult brain and is reproducible across several Down syndrome models. Using partially trisomic embryonic stem (ES) cells, Canzonetta et al. (2008) mapped this effect to a 3-gene segment of human chromosome 21 containing DYRK1A (600855). The authors independently identified the same locus as the most significant expression quantitative trait locus (eQTL) controlling REST expression in the human genome. Canzonetta et al. (2008) found that specifically silencing the third copy of DYRK1A rescued Rest levels, and demonstrated altered Rest expression in response to inhibition of DYRK1A expression or kinase activity, and in a transgenic Dyrk1a mouse. The authors observed that undifferentiated trisomy 21 ES cells showed DYRK1A-dose-sensitive reductions in levels of some pluripotency regulators, including Nanog (607937) and Sox2 (184429), causing premature expression of transcription factors driving early endodermal and mesodermal differentiation, partially overlapping downstream effects of Rest heterozygosity. The ES cells produced embryoid bodies with elevated levels of the primitive endoderm progenitor marker Gata4 (600576) and a strongly reduced neuroectodermal progenitor compartment. Canzonetta et al. (2008) concluded that DYRK1A-mediated deregulation of REST is a very early pathologic consequence of trisomy 21 with potential to disturb the development of all embryonic lineages, warranting closer research into its contribution to Down syndrome pathology and rationales for therapeutic approaches.

Letourneau et al. (2014) studied the transcriptome of fetal fibroblasts from a pair of monozygotic twins discordant for trisomy 21 and showed that the differential expression between the twins was organized in domains along all chromosomes that are either upregulated or downregulated. These gene expression dysregulation domains (GEDDs) can be defined by the expression level of their gene content, and are well conserved in induced pluripotent stem cells derived from the twins' fibroblasts. Comparison of the transcriptome of the Ts65Dn mouse model of Down syndrome and normal littermate mouse fibroblasts also showed GEDDs along the mouse chromosomes that were syntenic in human. The GEDDs correlated with the lamina-associated domains (LADs) and the replication domains of mammalian cells. The overall position of LADs was not altered in trisomic cells; however, the H3K4me3 profile of the trisomic fibroblasts was modified and accurately followed the GEDD pattern. Letourneau et al. (2014) concluded that the nuclear compartments of trisomic cells undergo modifications of the chromatin environment influencing the overall transcriptome, and that GEDDs may therefore contribute to some trisomy 21 phenotypes. Letourneau et al. (2014) suggested that this effect may originate from the chromosome 21 protein HMGN1 (163920). The correlation of GEDDs with the replication time domains and a prolonged permissive chromatin state in trisomic cells raised the question of an excess of background transcription in trisomic cells. Letourneau et al. (2014) proposed that the overexpression of 1 or more human chromosome 21 candidate gene(s) modifies the chromatin environment of the nuclear compartments in trisomic cells. These modifications would lead to a general perturbation of the transcriptome that could explain some Down syndrome phenotypes. Alternatively, the GEDDs could be the result of the additional chromosomal material of trisomy 21. The prediction of this latter hypothesis is that other trisomies may have a similar effect on the dysregulation of gene expression, which remained to be studied.

Gimenez-Barcons et al. (2014) noted that Down syndrome is strongly associated with autoimmune disease. The transcription factor AIRE (607658), which is encoded on chromosome 21q22.3, regulates promiscuous gene expression (pGE) and thus plays a crucial role in autoimmunity. Gimenez-Barcons et al. (2014) assessed expression of AIRE in thymus samples from 19 patients with Down syndrome and 21 euploid controls. Despite the presence of trisomy 21 and 3 copies of AIRE, AIRE expression was significantly reduced by 2-fold in Down syndrome thymuses compared with controls. Decreased expression of AIRE was associated with reduced pGE because expression of the tissue-restricted antigens CHRNA1 (100690), GAD1 (605363), PLP1 (300401), KLK3 (176820), SAG (181031), TG (188450), and TSHR (603372) was reduced. More than half of the Down syndrome patients, and none of the controls, developed thyroid dysfunction over an approximately 20-year period, with 10 patients developing hypothyroidism and 1 developing Graves disease (see 275000). Patient thymuses contained significantly lower levels of AIRE and TG, an antigen to which tolerance is typically lost in autoimmune thyroiditis, leading to hypothyroidism. Gimenez-Barcons et al. (2014) concluded that AIRE and pGE have fundamental roles in predisposing individuals with Down syndrome to autoimmunity.

Using male mice doubly heterozygous for a 16;17 and a 9;16 translocation in crosses with females with a normal complement of 40 acrocentric chromosomes, Miyabara et al. (1982) generated litters with a high incidence of trisomy 16 in order to investigate the embryonic phenotype. A number of authors, including Polani and Adinolfi (1980), suggested that trisomy 16 in the mouse was likely to be homologous to trisomy 21 in humans since the loci SOD1 (Francke and Taggart, 1979), IFRC (Cox et al., 1980), and PRGS (Cox et al., 1981) are shared between these chromosomes in the 2 species. The frequency of trisomic embryos declined with advancing gestation; at day 14, 27.3% were recognized to be trisomic whereas only 4.3% of 20-day embryos were shown to be trisomy 16. General hypoplasia and developmental delay were noted together with early edema, all features compatible with the human syndrome. Malformations included a high incidence of hydronephrosis and complex heart anomalies. Like its human counterpart, atrioventricular septal defect in mice was often associated with outflow tract defects including truncus arteriosus, interrupted aortic arch, and double outlet right ventricle. In a subsequent review, Miyabara (1990) noted phenotypic overlap with DiGeorge syndrome (188400), which may reflect homology with the 22q11 region. The incidence of heart defects was higher in the mouse model than in humans, perhaps a result of earlier examination and the complexity of chromosomal homology. They noted that another influence is the genetic background. Against the NIMR background, Miyabara et al. (1982) found 56% AVSD cases, whereas against C57BL/6, Miyabara et al. (1984) found 95.5% cases.

Shinohara et al. (2001) used microcell-mediated chromosome transfer to create chimeric mice containing human chromosome 21. Fluorescence in situ hybridization and PCR-based DNA analysis revealed that chromosome 21 was substantially intact but had sustained a small deletion. The freely segregating chromosome 21 was lost during development in some tissues, resulting in a panel of chimeric mice with varying degrees of mosaicism. The chimeric mice showed a high correlation between retention of chromosome 21 in the brain and impairment in learning or emotional behavior by open-field, contextual fear conditioning, and forced swim tests. A significant number of the chimeric fetuses exhibited both thymic hypoplasia and conotruncal cardiac defects, and most of these animals also exhibited atrioventricular canal malformations.

Altafaj et al. (2001) generated transgenic mice overexpressing the full-length cDNA of Dyrk1A (600855). Dyrk1A mice exhibited delayed craniocaudal maturation with functional consequences in neuromotor development. Dyrk1A mice also showed altered motor skill acquisition and hyperactivity, which was maintained to adulthood. In the Morris water maze, Dyrk1A mice showed a significant impairment in spatial learning and cognitive flexibility, indicative of hippocampal and prefrontal cortex dysfunction. In the more complex repeated reversal learning paradigm, this defect was specifically related to reference memory, whereas working memory was almost unimpaired. The authors suggested a causative role of DYRK1A in mental retardation and in motor anomalies of DS.

Trisomy 21 results in cerebellar dysmorphism with direct parallels in the Ts65Dn (partial trisomy) mouse. Despite pronounced changes in morphology, cerebellar function is not markedly different. Saran et al. (2003) distinguished trisomic and euploid murine cerebellar transcriptomes by microarray analysis. Changes in expression of individual genes were very subtle, but the differences in respective transcriptome phenotypes extended deeply into the set of nearly 7,000 probes located throughout the genome. Examination of the discriminating genes in 2 independent experiments suggested that the global perturbation may include a significant stochastic component. Thus, dosage imbalance of the 124 genes in Ts65Dn mice altered the expression of thousands of genes to create a variable trisomic transcriptome.

Olson et al. (2004) used chromosome engineering to create mice that were trisomic or monosomic for only the mouse chromosome segment orthologous to the Down syndrome critical region and assessed dysmorphologies of the craniofacial skeleton that showed direct parallels with Down syndrome in mice with a larger segmental trisomy. The Down syndrome critical region genes were not sufficient and were largely not necessary to produce the facial phenotype. Olson et al. (2004) concluded that their results refuted specific predictions of the prevailing hypothesis of gene action in Down syndrome.

O'Doherty et al. (2005) generated a transspecies aneuploid mouse line that stably transmits a freely segregating, almost complete human chromosome 21. This transchromosomic mouse line, Tc1, is a model of trisomy 21, which manifests as Down syndrome in humans, and has phenotypic alterations in behavior, synaptic plasticity, cerebellar neuronal number, heart development, and mandible size that relate to human Down syndrome.

Roper et al. (2006) found that a deficit in cerebellar granule cell neurons in a mouse model of Down syndrome was associated with reduced mitogenic response of granule cell precursors to Hedgehog protein signaling in early postnatal development. Systemic treatment of newborn trisomic mice with a small molecule agonist of the Hedgehog signaling pathway increased mitosis and restored the granule cell precursor population in vivo.

In Ts65Dn and Ts1Cje mouse models of Down syndrome, Salehi et al. (2006) found that increased dosage of the App gene markedly decreased retrograde transport of nerve growth factor (NGF; 162030), thus resulting in degeneration of cholinergic neurons in the basal forebrain. NGF-containing early endosomes were enlarged in cholinergic axons of the Ts65Dn mice and their App content was increased. The findings demonstrated a pathogenic mechanism for Down syndrome whereby disrupted axonal transport in certain neurons results in neuronal degeneration.

Sussan et al. (2008) used mouse models of Down syndrome and of cancer in a biologic approach to investigate the relationship between trisomy and the incidence of intestinal tumors. Apc(Min) (611731)-mediated tumor number was determined in aneuploid mouse models Ts65Dn, Ts1Rhr, and Ms1Rhr. Trisomy for orthologs of about half of the genes on chromosome 21 (Hsa21) in Ts65Dn mice or just 33 of these genes in Ts1Rhr mice resulted in a significant reduction in the number of intestinal tumors. In Ms1Rhr, segmental monosomy for the same 33 genes that are triplicated in Ts1Rhr resulted in an increased number of tumors. Further studies demonstrated that the Ets2 gene (164740) contributed most of the dosage-sensitive effect on intestinal tumor number. The action of Est2 as a repressor when it is overexpressed differs from tumor suppression, which requires normal gene function to prevent cellular transformation. Sussan et al. (2008) suggested that upregulation of Ets2 and, potentially, other genes involved in this kind of protective effect may provide a prophylactic effect in all individuals, regardless of ploidy.

Wilson et al. (2008) used the Tc1 mouse model of Down syndrome to determine whether, on a chromosomal scale, interspecies differences in transcriptional regulation are primarily directed by human genetic sequence or mouse nuclear environment. Virtually all transcription factor-binding locations, landmarks of transcription initiation, and the resulting gene expression observed in human hepatocytes were recapitulated across the entire human chromosome 21 in the mouse hepatocyte nucleus. Wilson et al. (2008) concluded that thus, in homologous tissues, genetic sequence is largely responsible for directing transcriptional programs; interspecies differences in epigenetic machinery, cellular environment, and transcription factors themselves play secondary roles.

Voronov et al. (2008) found altered phosphatidylinositol-4,5-bisphosphate metabolism in the brains of Ts65Dn mice. The defect could be rescued by restoring Synj1 (604297) to disomy in Ts65Dn mice and could also be recapitulated in transgenic mice overexpressing Synj1. The transgenic mice exhibited deficits in performance of the Morris water maze task, suggesting that perturbation of this signaling pathway may contribute to brain dysfunction