Alport Syndrome 2, Autosomal Recessive
A number sign (#) is used with this entry because autosomal recessive Alport syndrome-2 (ATS2) is caused by homozygous or compound heterozygous mutation in the COL4A3 (120070) or the COL4A4 (120131) gene, both of which map to chromosome 2q36.
DescriptionAlport syndrome is a hereditary disorder of the basement membrane, resulting in a glomerulonephropathy causing renal failure. Progressive deafness and ocular anomalies may also occur (Mochizuki et al., 1994; Colville et al. (1997)).
For a general phenotypic description of Alport syndrome, see the X-linked dominant form (ATS1; 301050). Approximately 85% of cases of Alport syndrome are X-linked and about 15% are autosomal recessive; autosomal dominant inheritance (ATS3; 104200) is rare (van der Loop et al., 2000).
See also benign familial hematuria (BFH; 141200), a similar but milder disorder.
Clinical FeaturesPasswell et al. (1981) described a girl, born of first-cousin parents, who presented in the first year of life with failure to thrive and was found to have nephritis and deafness. She showed the characteristic electron microscopic feature of Alport syndrome, including thickening and splitting of the basement membranes of both the glomeruli and the tubules into thin layers, with accumulation of electron dense particles within this network. The parents were unaffected, but 2 maternal uncles had chronic nephritis and neurosensory deafness. An unusual feature was Fanconi syndrome in the proband.
Mochizuki et al. (1994) reported 4 unrelated families with autosomal recessive Alport syndrome. In 1 family, a brother and sister were affected. The girl developed hematuria at age 4 and sensorineural deafness. She received a renal allograft at age 10 and developed anti-glomerular basement membrane (GBM) nephritis 6 months later. Her brother had hematuria, deafness, and deteriorating renal function. An 11-year-old Belgian girl, born of consanguineous parents, developed proteinuria and microhematuria at age 7 and end-stage renal disease at age 11. At age 11, she had renal transplant from her mother, and no rejection or anti-GBM nephritis had developed by age 16. At age 13, an audiogram showed bilateral sensorineural hearing loss. Both parents were unaffected and had normal renal function and urinalysis. In the third family, 2 sisters were affected: end-stage renal disease developed in the older sister at the age of 14, but no deafness or ocular abnormalities were observed. Renal biopsy at age 7 years showed thinning and focal thickening of the glomerular basement membrane. The other sister was noted to have microscopic hematuria at age 5, and developed nephrotic syndrome without a decrease in renal function at age 11. She also had no deafness or ocular abnormalities. Her consanguineous parents, Berbers from Algeria, tested negative for hematuria and proteinuria. The last proband was from a small village in Italy and had 2 affected sisters, both of whom had died of renal failure at age 12 and 8 years.
Evidence of Digenic Inheritance
Using massively parallel sequencing, Mencarelli et al. (2015) identified 11 patients with Alport syndrome who had pathogenic mutations in 2 of the 3 collagen IV genes. Seven patients had a combination of mutations in COL4A3 (120070) and COL4A4 (120131). In 5 of these patients (families 1 through 5), the 2 mutations were inherited independently (like in trans), and in the other 2 (families 6 and 7) the mutations were inherited on the same chromosome (like in cis). In families 1 through 5 individuals with 2 heterozygous mutations had more severe phenotypes than those with a single heterozygous mutation. Individuals carrying a heterozygous mutation only in COL4A3 had hematuria. Individuals carrying a heterozygous mutation only in COL4A4 had phenotypes ranging from hematuria to end-stage renal disease. In families 6 and 7, the phenotype in individuals carrying 2 mutations was more severe than expected for the classic autosomal dominant form, with 1 affected individual from each of these families progressing toward end-stage renal disease at 40 years of age. Mencarelli et al. (2015) remarked that this is later than the mean age expected in the autosomal recessive form of Alport syndrome (31 years), but earlier than expected in the autosomal dominant form (56 years). Mencarelli et al. (2015) concluded that these observations fit well with the stoichiometry of the molecules of the triple helix. In double heterozygotes, about 75% of triple-helix molecules are expected to be defective, which is greater than 50% in heterozygotes and less than 100% in homozygotes or hemizygotes.
Other FeaturesColville et al. (1997) examined the eyes of a family with autosomal recessive Alport syndrome. Four of the 8 offspring of a consanguineous marriage had renal failure and deafness by the age of 20 years. Studies of linkage to the COL4A5 (303630)/COL4A6 (303631) locus yielded strongly negative lod scores (excluding the X-linked form), whereas linkage to an intragenic marker for the COL4A3/COL4A4 locus showed positive lod scores consistent with the autosomal recessive form. All 4 affected members had anterior lenticonus, and the 3 who were examined had a dot-and-fleck retinopathy. Colville et al. (1997) concluded that the ocular manifestations of autosomal recessive Alport syndrome are identical to those of the X-linked form.
Rhys et al. (1997) observed 3 brothers with Alport syndrome and a history of spontaneous attacks of recurrent corneal erosion (RCE). In 2 of them, 2 episodes over a period of 1 to 3 years had occurred; the third brother had suffered approximately 60 episodes over the previous 10 years. To assess the prevalence of RCE in Alport syndrome, Rhys et al. (1997) surveyed 41 patients with Alport syndrome and renal failure and 67 control patients transplanted for another form of nephropathy. A history of RCE, first manifested between the ages of 12 and 21 years, was obtained in 7 Alport syndrome patients but in only 1 control patient (p = 0.003).
InheritanceIn a study of 41 families with stringent criteria for Alport syndrome, Feingold et al. (1985) found 4 families in which autosomal recessive inheritance seemed likely because of parental consanguinity and unaffected parents. The criteria were proven for renal disease with hematuria in at least 2 relatives, neural hearing loss in at least 1 affected person, and evolution to renal failure in at least 1 affected person.
As reviewed by Gubler et al. (1995), autosomal recessive transmission of Alport syndrome was suggested for a small percent of kindreds because of the finding of parental consanguinity, absence of severe symptoms in parents, and equal severity of the disease in males and females.
Anazi et al. (2014) reported an unusual mode of transmission in a family in which 3 sibs, born of double-cousin consanguineous parents, had Alport syndrome. After autozygosity mapping failed to yield definitive results, exome sequencing revealed compound heterozygous truncating mutations in the COL4A4 gene that segregated with the disorder in the family. One mutation was found in the father, but the other mutation was determined to result from maternal gonadal mosaicism. Anazi et al. (2014) discussed the implications of this rare occurrence for genetic counseling.
Molecular GeneticsIn affected members of 4 unrelated families with autosomal recessive Alport syndrome, Mochizuki et al. (1994) identified homozygous mutations in the COL4A3 (120070.0001 and 120070.0004) or the COL4A4 (120131.0001-120131.0002) gene.
Lemmink et al. (1994) identified compound heterozygous nonsense mutations in the COL4A3 gene (120070.0002 and 120070.0003) in a patient with autosomal recessive Alport syndrome. Another variant (L36P) was identified, although it was determined not to be pathogenic. Autosomal recessive inheritance due to pathogenic COL4A3 mutations accounted for at least 13% of 22 Alport syndrome cases in this sample. All cases with COL4A3 mutations had renal histology and high-frequency hearing loss typical of the X-linked form of Alport syndrome.
Gubler et al. (1995) stated that up to 15% of Alport syndrome cases represent the autosomal recessive form due to mutations in either the COL4A3 or the COL4A4 gene.
Clinical ManagementComplications of Renal Transplantation
Milliner et al. (1982) estimated that approximately 1 to 5% of Alport patients who receive transplants develop a specific anti-GBM nephritis, subsequently leading to loss of the renal graft.
Kalluri et al. (1994) found that posttransplant anti-GBM alloantibodies from an X-linked Alport patient with complete COL4A5 gene deletion were specifically targeted to the COL4A3 chain. In further studies, Kalluri et al. (1995) demonstrated posttransplant anti-COL4A3 alloantibodies in a patient with autosomal recessive Alport syndrome caused by deletion of the last 198 amino acids of the COL4A3. The absence of the COL4A3 chain in the GBM of patients with both these forms of Alport syndrome, due either to a failure of synthesis or a failure of assembly, presumably leads to a loss of immunologic tolerance for the COL4A3 NC1 domain in transplanted allografts.
In a review of mutations that had been identified in the type IV collagen genes in patients with Alport syndrome, Lemmink et al. (1997) found data on 46 patients with transplants, among whom there were 41 with a COL4A5 mutation, 4 with a COL4A3 mutation, and 1 with a COL4A4 mutation. All patients except 1 had juvenile Alport syndrome. In 9 patients with transplants (20% of the total number of transplants), a specific anti-GBM nephritis was detected. Of these 9, 8 carried large deletions or premature stop codons, which were predicted to result in COL4A3 or COL4A5 proteins truncated within the noncollagenous (NC) domain. The exception was a splice mutation in COL4A5 resulting in an mRNA without exon 38. Four patients identified with COL4A3 mutations had had transplants and 3 of them developed an anti-GBM nephritis. These data suggested that Alport syndrome patients with a type IV collagen mutation resulting in absence of the NC domain have an increased risk of developing anti-GBM nephritis after renal transplantation.
Kalluri et al. (1997) developed a new mouse model of human anti-GBM disease to characterize better the genetic determinants of cell-mediated injury. The findings in studies of the model suggested that anti-GBM antibodies in mice facilitate disease only in MHC haplotypes capable of generating nephritogenic lymphocytes with special T-cell repertoires.
PathogenesisGubler et al. (1995) used an immunofluorescence technique to analyze the distribution of different type IV collagen chains in renal and skin basement membranes of 12 Alport syndrome patients belonging to 11 unrelated kindreds in which autosomal recessive inheritance had been demonstrated (3 kindreds) or suggested by clinical and genealogic data (8 kindreds). The renal and skin distribution was normal in 1 patient with a COL4A4 mutation. A particular pattern of distribution was observed in the other patients: co-absence of alpha-3(IV), alpha-4(IV), and alpha-5(IV) chains in the glomerular basement membrane, and the presence of the alpha-5(IV) chain in a series of extraglomerular basement membranes, including capsular, collecting ducts, and epidermal basement membranes, a combination never observed in X-linked Alport syndrome. This immunohistochemical pattern correlated with the specific distribution of the 3 types of collagen IV chains within extraglomerular basement membranes.
Population GeneticsWebb et al. (2014) identified a homozygous 24-bp deletion in the COL4A3 gene (c.40_63del; 120070.0011) in 3 sisters, born of unrelated parents of Ashkenazi Jewish descent, with autosomal recessive Alport syndrome. Population analysis yielded a carrier frequency of 0.55% (1 in 183) among Ashkenazi Jewish individuals, and haplotype analysis indicated a founder effect. Functional studies of the variant were not performed, but the parents were unaffected, suggesting that heterozygosity for this mutation does not predispose to disease.