ORPHA: 63, 88919; DO: 0110033;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q36.3 | Alport syndrome 2, autosomal recessive | 203780 | Autosomal recessive | 3 | COL4A4 | 120131 |
A number sign (#) is used with this entry because of evidence that autosomal recessive Alport syndrome-2 (ATS2) is caused by homozygous or compound heterozygous mutation in the COL4A4 gene (120131) on chromosome 2q36.
Another form of autosomal recessive Alport syndrome (ATS3B; 620536) results from homozygous or compound heterozygous mutation in the COL4A3 gene (120070) on chromosome 2q36.
Autosomal recessive Alport syndrome-2 (ATS2) 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 (ATS3A; 104200) is rare (van der Loop et al., 2000).
See also benign familial hematuria (BFH; 141200), a similar but milder disorder.
Mochizuki et al. (1994) reported 2 unrelated families with autosomal recessive Alport syndrome and mutation in the COL4A4 gene. In family BE, 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. Their consanguineous parents, Berbers from Algeria, tested negative for hematuria and proteinuria. The proband from family GA had albuminuria and hematuria at age 8 years. Renal function deteriorated progressively; hemodialysis was started at age 18 years and she underwent kidney transplant. Her 2 affected sisters died of renal failure at age 12 and 8 years. The parents shared the same surname and originated from the same small village in Italy. The mother had normal renal function and no urinary abnormalities at age 53; in the father, who had normal renal function, microhematuria had been found intermittently.
Colville 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.
To assess the prevalence of recurrent corneal erosion (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, 1 with probable autosomal recessive inheritance, but in only 1 control patient (p = 0.003).
Boye et al. (1998) identified 10 patients from 3 families with autosomal recessive Alport syndrome and mutation in the COL4A4 gene. All of the patients had features of severe Alport syndrome, including deafness. Five of them, aged 22 to 34 years, had end-stage renal disease or chronic renal failure, and the 5 others, all aged less than 28 years, presented hematuria and proteinuria. Heterozygotes had either no hematuria or permanent microscopic hematuria with normal renal function, even at 90 years of age. One heterozygous individual had microscopic, with episodes of macroscopic, hematuria. Renal biopsy of 1 heterozygote at age 27 years revealed thin basement membranes.
The transmission pattern of ATS2 in the families reported by Mochizuki et al. (1994) was consistent with autosomal recessive inheritance.
In 3 sibs with autosomal recessive Alport syndrome reported by Anazi et al. (2014), 1 mutation was found in the father, and the other mutation was determined to result from maternal gonadal mosaicism.
In affected members of 2 unrelated families with autosomal recessive Alport syndrome, Mochizuki et al. (1994) identified homozygous mutations in the COL4A4 (120131.0001-120131.0002) gene.
Boye et al. (1998) identified 10 pathogenic mutations in the COL4A4 gene in 8 patients with autosomal recessive Alport syndrome. There were 2 nonsense, 3 frameshift, 1 in-frame deletion, 2 splicing, and 2 missense mutations.
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.
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.
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.
Anazi, S., Al-Sabban, E., Alkuraya, F. S. Gonadal mosaicism as a rare cause of autosomal recessive inheritance. Clin. Genet. 85: 278-281, 2014. [PubMed: 23551117] [Full Text: https://doi.org/10.1111/cge.12156]
Boye, E., Mollet, G., Forestier, L., Cohen-Solal, L., Heidet, L., Cochat, P., Grunfeld, J.-P., Palcoux, J.-B., Gubler, M.-C., Antignac, C. Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport syndrome. Am. J. Hum. Genet. 63: 1329-1340, 1998. [PubMed: 9792860] [Full Text: https://doi.org/10.1086/302106]
Colville, D., Savige, J., Morfis, M., Ellis, J., Kerr, P., Agar, J., Fasset, R. Ocular manifestations of autosomal recessive Alport syndrome. Ophthal. Genet. 18: 119-128, 1997. [PubMed: 9361309] [Full Text: https://doi.org/10.3109/13816819709057125]
Gubler, M., Levy, M., Broyer, M., Naizot, C., Gonzales, G., Perrin, D., Habib, R. Alport's syndrome: a report of 58 cases and a review of the literature. Am. J. Med. 70: 493-505, 1981. [PubMed: 7211891] [Full Text: https://doi.org/10.1016/0002-9343(81)90571-4]
Gubler, M.-C., Knebelmann, B., Beziau, A., Broyer, M., Pirson, Y., Haddoum, F., Kleppel, M. M., Antignac, C. Autosomal recessive Alport syndrome: immunohistochemical study of type IV collagen chain distribution. Kidney Int. 47: 1142-1147, 1995. [PubMed: 7783412] [Full Text: https://doi.org/10.1038/ki.1995.163]
Mencarelli, M. A., Heidet, L., Storey, H., van Geel, M., Knebelmann, B., Fallerini, C., Miglietti, N., Antonucci, M. F., Cetta, F., Sayer, J. A., van den Wijngaard, A., Yau, S., Mari, F., Bruttini, M., Ariani, F., Dahan, K., Smeets, B., Antignac, C., Flinter, F., Renieri, A. Evidence of digenic inheritance in Alport syndrome. J. Med. Genet. 52: 163-174, 2015. [PubMed: 25575550] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102822]
Mochizuki, T., Lemmink, H. H., Mariyama, M., Antignac, C., Gubler, M.-C., Pirson, Y., Verellen-Dumoulin, C., Chan, B., Schroder, C. H., Smeets, H. J., Reeders, S. T. Identification of mutations in the alpha-3(IV) and alpha-4(IV) collagen genes in autosomal recessive Alport syndrome. Nature Genet. 8: 77-81, 1994. [PubMed: 7987396] [Full Text: https://doi.org/10.1038/ng0994-77]
Rhys, C., Snyers, B., Pirson, Y. Recurrent corneal erosion associated with Alport's syndrome. Kidney Int. 52: 208-211, 1997. [PubMed: 9211364] [Full Text: https://doi.org/10.1038/ki.1997.321]
van der Loop, F. T. L., Heidet, L., Timmer, E. D. J., van den Bosch, B. J. C., Leinonen, A., Antignac, C., Jefferson, J. A., Maxwell, A. P., Monnens, L. A. H., Schroder, C. H., Smeets, H. J. M. Autosomal dominant Alport syndrome caused by a COL4A3 splice site mutation. Kidney Int. 58: 1870-1875, 2000. [PubMed: 11044206] [Full Text: https://doi.org/10.1111/j.1523-1755.2000.00358.x]