Autosomal dominant Alport syndrome: molecular analysis of the COL4A4 gene and clinical outcome.
BACKGROUND
Alport syndrome is a clinically and genetically heterogeneous nephropathy characterized by glomerular basement membrane lesions often associated with hearing loss and ocular anomalies. While the X-linked and the autosomal recessive forms are well known, the autosomal dominant form is not well acknowledged.


METHODS
We have clinically investigated 38 patients with a diagnosis of autosomal dominant Alport syndrome belonging to eight different families. The analysis of the COL4A4 gene was performed by denaturing high performance liquid chromatography and automated DNA sequencing.


RESULTS
In our cohort of patients, only 24.3% (9/37) reached end-stage renal disease, at the mean age of 51.2 years. Four patients had hearing loss (13.3%) and none ocular changes. Molecular analysis revealed eight novel private COL4A4 gene mutations: three frameshift, three missense and two splice-site mutations.


CONCLUSIONS
These data indicate autosomal dominant Alport syndrome as a disease with a low risk of ocular and hearing anomalies but with a significant risk to develop renal failure although at an older age than the X-linked form. We were unable to demonstrate a genotype-phenotype correlation. Altogether, these data make difficult the differential diagnosis with the benign familial haematuria due to heterozygous mutations of COL4A4 and COL4A3, especially in young patients, and with the X-linked form of Alport syndrome in families where only females are affected. A correct diagnosis and prognosis is based on a comprehensive clinical investigation in as many family members as possible associated with a broadly formal genetic analysis of the pedigree.
Marcocci
Elena
E
Medical Genetics, Department of Molecular Biology, University of Siena, Siena, Italy.
Uliana
Vera
V
Bruttini
Mirella
M
Artuso
Rosangela
R
Silengo
Margherita Cirillo
MC
Zerial
Marlenka
M
Bergesio
Franco
F
Amoroso
Antonio
A
Savoldi
Silvana
S
Pennesi
Marco
M
Giachino
Daniela
D
Rombolà
Giuseppe
G
Fogazzi
Giovanni Battista
GB
Rosatelli
Cristina
C
Martinhago
Ciro Dresch
CD
Carmellini
Mario
M
Mancini
Roberta
R
Di Costanzo
Giuseppina
G
Longo
Ilaria
I
Renieri
Alessandra
A
Mari
Francesca
F
D000368:Aged; D024141:Collagen Type IV / Q000235:genetics*; D003937:Diagnosis, Differential; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D006417:Hematuria / Q000175:diagnosis / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009394:Nephritis, Hereditary / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D011379:Prognosis
C466620:COL4A4 protein, human; D024141:Collagen Type IV