Alport Syndrome 3, Autosomal Dominant

A number sign (#) is used with this entry because autosomal dominant Alport syndrome-3 (ATS3) is caused by heterozygous mutation in the COL4A3 gene (120070) on chromosome 2q36.

Description

Alport syndrome classically comprises nephritis, often progressing to renal failure, and sensorineural hearing loss (Alport, 1927).

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 (ATS2; 203780); autosomal dominant inheritance is rare (van der Loop et al., 2000).

Also see benign familial hematuria (BFH; 141200), a similar but milder disorder also caused by mutation in the COL4A3 gene.

Clinical Features

Jefferson et al. (1997) reported an Irish family with apparent autosomal dominant inheritance of Alport syndrome. The proband was a young man who presented with asymptomatic microhematuria and hypertension. His renal function deteriorated and he reached end-stage renal failure at age 35 years. He also had mild high-tone deafness. His father had a long history of microhematuria and hypertension, with documented renal failure before his death at age 68 years from myocardial infarction. Screening of other sibs of the proband showed 4 sisters and 1 brother with microhematuria and proteinuria. All had normal audiograms. The mother had no evidence of hematuria or renal dysfunction. Electron microscopy of affected individuals showed an irregular and thickened glomerular basement membrane, characteristic of Alport syndrome.

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 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. 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.

Inheritance

Evans et al. (1980) reviewed the inheritance of Alport syndrome and noted that early reports of dominant inheritance (e.g., Shaw and Glover, 1961; Perkoff et al. (1951, 1958)) were later considered to be more consistent with X-linked dominant inheritance (O'Neill et al., 1978). However, Evans et al. (1980) noted the variation in inheritance patterns and reported a family with male-to-male transmission, suggesting genetic heterogeneity.

Feingold et al. (1985) also suggested that there is an autosomal dominant form of Alport syndrome.

Mapping

By linkage analysis of a family with apparent autosomal dominant inheritance of Alport syndrome, Jefferson et al. (1997) found linkage to a region on chromosome 2q in the vicinity of the COL4A3 and COL4A4 genes. However, no pathogenic mutations were identified by direct sequencing. The authors hypothesized that heterozygous mutations in these genes could result in a less severe phenotype than that of autosomal recessive Alport, which is caused by homozygous or compound heterozygous mutations in these genes. They also noted that heterozygous mutations in these genes result in benign familial hematuria (BFH; 141200), which does not result in renal failure. Jefferson et al. (1997) postulated that mutations in the type IV collagen genes can cause a spectrum of disease, ranging from BFH to autosomal dominant and recessive forms of Alport syndrome. Such a variation in clinical expression due to mutations in collagen genes is well recognized.

Molecular Genetics

In affected members of a family with autosomal dominant Alport syndrome reported by Jefferson et al. (1997), van der Loop et al. (2000) identified a heterozygous mutation in the COL4A3 gene (120070.0009). The mutation resulted in a splice site mutation and a mutant protein with a deletion in the collagenous domain. The mutation was found in all 6 affected individuals and in none of 8 unaffected individuals. Since the noncollagenous domain remained intact, this mutant chain may be incorporated and distort the collagen triple helix, causing a dominant effect. The finding of a COL4A3 mutation in autosomal dominant Alport syndrome completed the broad spectrum of type IV collagen mutations, ranging from no effect at all and familial benign hematuria to mild autosomal dominant and severe autosomal recessive Alport syndrome.

In a mother and daughter with autosomal dominant Alport syndrome, Heidet et al. (2001) identified a heterozygous mutation in the COL4A3 gene (G1167R; 120070.0010). The daughter developed end-stage renal failure at age 23 years. Her mother had microscopic hematuria and proteinuria, but still had normal renal function at age 52 years, although renal biopsy showed thinning of and splitting of the glomerular basement membrane.