Three novel COL4A4 mutations resulting in stop codons and their clinical effects in autosomal recessive Alport syndrome.

Autosomal recessive Alport syndrome is caused by mutations in the COL4A3 and COL4A4 genes which code for the alpha3 and alpha4 chains of type IV collagen. These mutations result in haematuria, progressive renal impairment and often hearing loss, lenticonus and retinopathy. We describe here the mutations demonstrated by screening the 47 coding exons of the COL4A4 gene in six families with autosomal recessive Alport syndrome using PCR-single stranded conformational polymorphism (SSCP) analysis. Six sequence variants were identified. These included three novel mutations (2846delG, 2952delG and S969X) in exons 30 - 32 that all resulted in premature stop codons. These mutations were demonstrated in the heterozygous form in 3 families, and the S969X mutation was also present in the homozygous form in one of the two consanguinous families. These three mutations accounted for 40% (4/10) of the total mutant alleles in the six families studied. Six of the seven (86%) individuals with autosomal recessive Alport syndrome who had these mutations in the compound heterozygous or homozygous forms developed renal failure in adulthood, as well as hearing loss and ocular abnormalities. Haematuria was present in 15 of the 17 (88%) heterozygous mutation carriers. The other non-pathogenic sequence variants noted in COL4A4 included a nonglycine missense variant (L1004P), an intronic variant (4731-8 T>C) and a neutral polymorphism (V1516V).

Dagher H ，Yan Wang Y ，Fassett R ，Savige J ... -  《-》

Alport syndrome. Molecular genetic aspects.

Hertz JM 《-》

Autosomal dominant Alport syndrome: molecular analysis of the COL4A4 gene and clinical outcome.

Marcocci E ，Uliana V ，Bruttini M ，Artuso R ，Silengo MC ，Zerial M ，Bergesio F ，Amoroso A ，Savoldi S ，Pennesi M ，Giachino D ，Rombolà G ，Fogazzi GB ，Rosatelli C ，Martinhago CD ，Carmellini M ，Mancini R ，Di Costanzo G ，Longo I ，Renieri A ，Mari F ... -  《-》

Detection of mutations in the COL4A5 gene by SSCP in X-linked Alport syndrome.

Alport syndrome is a progressive renal disease leading to chronic renal failure, which often is accompanied by sensorineural deafness and ophthalmological signs in the form of anterior lenticonus. The X-linked form of the disease is caused by mutations in the COL4A5 gene encoding the alpha5-chain of type IV-collagen. We performed mutation analysis of the COL4A5 gene by PCR-SSCP analysis of each of the 51 exons with flanking intronic sequences in 81 patients suspected of X-linked Alport syndrome including 29 clear X-linked cases, 37 cases from families with a pedigree compatible with X-linked inheritance, and 15 isolated cases. We found a mutation detection rate of 52% (42/81) (58% in males and 21% in females), and 69% (20/29) in families who clearly demonstrated X-linked inheritance. Thirty-six different mutations were found in 42 patients comprising 16 missense mutations, seven frameshifts, three in-frame deletions, four nonsense mutations, and six splice site mutations. Twenty-two of the mutations have not previously been reported. Furthermore, we found one non-pathogenic amino acid substitution, one rare variant in a non-coding region, and one polymorphism with a heterozygosity of 28%. Three de novo mutations were found, two of which were paternal and one of maternal origin.

Hertz JM ，Juncker I ，Persson U ，Matthijs G ，Schmidtke J ，Petersen MB ，Kjeldsen M ，Gregersen N ... -  《-》

Autosomal recessive Alport syndrome: an in-depth clinical and molecular analysis of five families.

Longo I ，Scala E ，Mari F ，Caselli R ，Pescucci C ，Mencarelli MA ，Speciale C ，Giani M ，Bresin E ，Caringella DA ，Borochowitz ZU ，Siriwardena K ，Winship I ，Renieri A ，Meloni I ... -  《NEPHROLOGY DIALYSIS TRANSPLANTATION》