Mental Retardation, Autosomal Dominant 31

A number sign (#) is used with this entry because of evidence that autosomal dominant mental retardation-31 (MRD31) is caused by heterozygous mutation in the PURA gene (600473) on chromosome 5q31.

Clinical Features

Lalani et al. (2014) reported 11 unrelated children with a similar neurodevelopmental disorder characterized by neonatal hypotonia, severely delayed psychomotor development, early-onset feeding difficulties, and significant respiratory insufficiency. Almost all had early-onset seizures, often myoclonic, but also generalized. Most had an abnormal EEG pattern, and 2 developed an epileptic encephalopathy consistent with a clinical diagnosis of Lennox-Gastaut syndrome. Hypomyelination or delayed myelination was noted on brain imaging studies in 4 individuals. Most patients were nonverbal and nonambulatory. Dysmorphic facial features were variable and nonspecific except for myopathic facies, often with open mouth and high-arched palate, nystagmus, and strabismus in many patients. Lalani et al. (2014) noted the phenotypic overlap with chromosome 5q31.3 microdeletion syndrome (Brown et al., 2013).

Hunt et al. (2014) reported 4 unrelated girls with neurodevelopmental delay. Two patients were severely affected, with hypotonia and apneic episodes at birth and severely delayed psychomotor development; neither could walk at ages 4 and 6 years, respectively, and both were essentially nonverbal. Both patients also had dysconjugate gaze and either seizures or seizure-like episodes. Brain MRI of both patients showed delayed myelination. The other 2 girls, 12 and 14 years of age, were able to walk with a broad-based gait and could speak with limited vocabulary. One was hypotonic and had seizure-like episodes. Brain imaging was normal in these 2 patients. All patients had mild but variable dysmorphic features, including hypotonic facies, prominent or high forehead, telecanthus, and upslanting palpebral fissures. One girl had gonadotropin-dependent precocious puberty and another had elevated prolactin levels soon after birth as well as blunted cortisol response to stress, suggesting that endocrine abnormalities may be part of the disorder.

The Deciphering Developmental Disorders Study (2015) reported 3 female patients with global developmental delay and various syndromic features who carried heterozygous de novo mutations in the PURA gene. One additionally had generalized hypotonia, cafe-au-lait spot, and unsteady gait; the second had delayed CNS myelination, epicanthus, short nose, deep philtrum, and edema; and the third had microcephaly, facial asymmetry, strabismus, hypertelorism, bilateral ptosis, overlapping toe, and anxiety.

Tanaka et al. (2015) reported 6 unrelated children, ranging from 6 months to 15 years of age, with moderate to severely delayed psychomotor development, lack of speech, and hypotonia. Two patients had seizure-like activity, and 5 had variable visual impairment, mainly esotropia and strabismus, although 1 had cortical visual impairment. Four patients had variable dysmorphic features, such as epicanthal folds, high-arched palate, dolichocephaly, hypertelorism, and broad forehead. Four had variable brain imaging abnormalities, including delayed myelination, enlarged ventricles, thin corpus callosum, and periventricular white matter changes.

Cytogenetics

Brown et al. (2013) reported 2 unrelated children with a severe neurodevelopmental disorder associated with de novo heterozygous deletions of chromosome 5q31.3. Both patients presented at birth with significant hypotonia, central apnea, and myoclonic jerks. One child was conceived by in vitro fertilization. One child was nonverbal and nonambulatory at 6 years of age, whereas the other was standing with support and able to indicate needs with gestures at age 2, both consistent with delayed psychomotor development. Brain imaging in both patients showed diffuse T2-weighted white matter lesions and shallow immature sulcation in the frontal lobes, with evidence of delayed myelination in 1 patient who underwent serial imaging. The shortest region of deletion overlap in these patients was 101 kb, including the PURA gene, which Brown et al. (2013) considered to be the best candidate for the phenotype.

Molecular Genetics

Lalani et al. (2014) identified de novo heterozygous mutations in the PURA gene (see, e.g., 600473.0001-600473.0005) in 11 (0.52%) of 2,117 pediatric patients with various neurodevelopmental disorders who underwent whole-exome sequencing. There were 4 truncating mutations, 5 missense mutations, and 2 in-frame deletions. Functional studies of the variants were not performed, but the presence of truncating mutations suggested at least a partial loss of protein function as responsible for the phenotype.

In 4 unrelated girls with MRD31, Hunt et al. (2014) identified 4 different de novo heterozygous mutations in the PURA gene (see, e.g., 600473.0006-600473.0008). Two mutations were truncating frameshifts, 1 was missense, and 1 was an in-frame deletion. The mutations were found by whole-exome sequencing; functional studies of the variants were not performed.

In 6 unrelated children with MRD31, Tanaka et al. (2015) identified 6 different de novo heterozygous mutations in the PURA gene (see, e.g., 600473.0008-600473.0010). The mutations, which were found by whole-exome sequencing, comprised missense, frameshift, and small intragenic deletions. Functional studies of the variants were not performed.

Animal Model

Khalili et al. (2003) found that Pura -/- mice appeared normal at birth, but at 2 weeks of age, they developed neurologic problems characterized by severe tremor and spontaneous seizures, and they died by 4 weeks. Regions of the hippocampus and cerebellum of Pura -/- mice showed severely lower numbers of neurons compared with wildtype littermates, and lamination of these regions was aberrant at time of death. Immunohistochemical analysis of Mcm7 (600592), a marker for DNA replication, revealed lack of proliferation of precursor cells in these regions in Pura -/- mice. Proliferation was also low or absent in several other tissues of Pura -/- mice, including those of myeloid lineage, whereas those of Pura +/- mice were intermediate. Evaluation of brain sections indicated reduced myelination and pathologic development of oligodendrocytes and astrocytes. At postnatal day 5, a critical time for cerebellar development, Pura and Cdk5 (123831) were both at peak levels in bodies and dendrites of Purkinje cells of wildtype mice, but both proteins were absent in dendrites of Pura -/- mice. Immunohistochemical analysis revealed dramatic reduction in both phosphorylated and nonphosphorylated neurofilaments in dendrites of the Purkinje cell layer and of synapse formation in the hippocampus. Khalili et al. (2003) concluded that PURA has a role in developmentally timed DNA replication in specific cell types.

Lalani et al. (2014) found that mutant Caenorhabditis elegans animals homozygous for a null allele of the PURA ortholog plp-1 were sterile and had defective locomotion compared to wildtype, suggesting a role for PURA in both germline and somatic neuronal tissues.