Genotype-phenotype correlation in von Hippel-Lindau families with renal lesions.
von Hippel-Lindau (VHL) disease arises from mutations in the VHL gene and predisposes patients to develop a variety of tumors in different organs. In the kidney, single or multiple cysts and renal cell carcinomas (RCC) may occur. Both inter- and intrafamilial heterogeneity in clinical expression are well recognized. To identify VHL-dependent genetic factors, we investigated the renal phenotype in 274 individuals from 126 unrelated VHL families in whom 92 different VHL mutations were characterized. The incidence of renal involvement was increased in families with mutations leading to truncated protein (MLTP) or large rearrangement, as compared to families with missense changes (81 vs. 63%, respectively; P=0.03). In the latter group, we identified two mutation cluster regions (MCRs) associated with a high risk of harboring renal lesions: MCR-1 (codons 74-90) and MCR-2 (codons 130-136). In addition, the incidence of RCC was higher in families with MLTP than in families with missense changes (75 vs. 57%; P=0.04). Furthermore, mutations within MCR-1 but not MCR-2 conferred genetic susceptibility to develop RCC. Overall, our data argued for a substantial contribution of the genetic change in the VHL gene to susceptibility to renal phenotype in VHL patients.
Gallou
Catherine
C
INSERM U 383, Hôpital Necker-Enfants Malades, Paris, France. catherine.gallou@necker.fr
Chauveau
Dominique
D
Richard
Stéphane
S
Joly
Dominique
D
Giraud
Sophie
S
Olschwang
Sylviane
S
Martin
Natacha
N
Saquet
Céline
C
Chrétien
Yves
Y
Méjean
Arnaud
A
Correas
Jean-Michel
JM
Benoît
Gérard
G
Colombeau
Pierre
P
Grünfeld
Jean-Pierre
JP
Junien
Claudine
C
Béroud
Christophe
C
D000328:Adult; D019943:Amino Acid Substitution; D002292:Carcinoma, Renal Cell / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D003062:Codon; D018389:Codon, Nonsense; D018388:Codon, Terminator; D005091:Exons / Q000235:genetics; D005260:Female; D005602:France / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D015994:Incidence; D052177:Kidney Diseases, Cystic / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D007680:Kidney Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010641:Phenotype; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D017434:Protein Structure, Tertiary; D012306:Risk; D017384:Sequence Deletion; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease / Q000235:genetics* / Q000473:pathology
D003062:Codon; D018389:Codon, Nonsense; D018388:Codon, Terminator; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human