COL4A3/COL4A4 Mutations and Features in Individuals with Autosomal Recessive Alport Syndrome

Abstract

Alport syndrome is an inherited disease characterized by hematuria, progressive renal failure, hearing loss, and ocular abnormalities. Autosomal recessive Alport syndrome is suspected in consanguineous families and when female patients develop renal failure. Fifteen percent of patients with Alport syndrome have autosomal recessive inheritance caused by two pathogenic mutations in either COL4A3 or COL4A4. Here, we describe the mutations and clinical features in 40 individuals including 9 children and 21 female individuals (53%) with autosomal recessive inheritance indicated by the detection of two mutations. The median age was 31 years (range, 6-54 years). The median age at end stage renal failure was 22.5 years (range, 10-38 years), but renal function was normal in nine adults (29%). Hearing loss and ocular abnormalities were common (23 of 35 patients [66%] and 10 of 18 patients [56%], respectively). Twenty mutation pairs (50%) affected COL4A3 and 20 pairs affected COL4A4. Of the 68 variants identified, 39 were novel, 12 were homozygous changes, and 9 were present in multiple individuals, including c.2906C.G (p.(Ser969*)) in COL4A4, which was found in 23% of the patients. Thirty-six variants (53%) resulted directly or indirectly in a stop codon, and all 17 individuals with early onset renal failure had at least one such mutation, whereas these mutations were less common in patients with normal renal function or late-onset renal failure. In conclusion, patient phenotypes may vary depending on the underlying mutations, and genetic testing should be considered for the routine diagnosis of autosomal recessive Alport syndrome.

HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease

“…Indeed, in homozygous ENU Col4a1 mice with exon 40 deletion, the a1(IV) chain mutation results in the absence of the collagen IV network in embryonic BMs responsible for embryonic lethality. 7,13 Therefore, as previously demonstrated in Alport syndrome, [21][22][23] the type of mutation and location of glycine substitution may influence the severity of the phenotype in COL4A1-related diseases.…”

A case of mild phenotype Alport syndrome caused by COL4A3 mutations

“…Storey et al explained that the structure of type IV collagen can vary for different patterns of gene mutation [11]. Although type IV collagen in the GBM is not formed by nonsense mutations or other mutations that insert a termination codon in the downstream region, type IV collagen with an abnormal structure may be formed by missense mutations.…”

“…These findings were associated with early onset renal failure. While missense mutations produced an abnormal GBM that was less likely to be deleterious and expressed the a5 chain, these mutations were associated with late-onset renal failure [11]. Therefore, we considered that the presence or absence of the a5 chain which varied with the pattern of gene mutation was related to the prognosis of renal function, regardless of whether patients have XLAS and ARAS.…”

The Interface of Genetics with Pathology in Alport Nephritis

“…In the last 2 decades, mutational screening for these genes has revealed that structural changes such as large deletions or nonsense mutations in COL4A5 are associated with early disease onset and the worst prognosis, whereas missense mutations are associated with less severe disease. 5 In this issue of JASN, Storey et al 6 report novel mutations of autosomal recessive AS that were not previously described; several individuals were identified with two COL4A3 or COL4A4 mutations. Storey et al found that 20% of their cohort of 205 patients with suspected AS or thin basement membrane disease had two pathogenic mutations in COL4A3 or COL4A4.…”

“…Diagnosis of AS can be relatively straightforward in patients with typical clinical presentation, family history, or characteristic pathology such as abnormal immunostaining patterns for COL4 a3-5 chains and basement membrane abnormalities on electron microscopy (EM). 2 On the other hand, diagnosis of AS can be quite challenging when the following occur: (1) the clinical presentation is atypical, (2) there is extreme variability in histologic findings, (3) there is an unexpected immunostaining pattern, (4) the family history is unavailable, (5) glomerular lesions such as FSGS are the only finding, 3 (6) other renal diseases that may confound pathologic findings are present, or (7) biopsy tissue is inadequate. Histologic features of thin basement membrane disease may be seen in the early presentation of AS and may pose a diagnostic dilemma.…”