Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database

被引:180
作者
Jeanpierre, C
Denamur, E
Henry, I
Cabanis, MO
Luce, S
Cécille, A
Elion, J
Peuchmaur, M
Loirat, C
Niaudet, P
Gubler, MC
Junien, C
机构
[1] Univ Rene Descartes, Hop Necker Enfants Malad, INSERM,U383, Clin Maurice Lamy, F-75743 Paris, France
[2] Univ Rene Descartes, Hop Necker Enfants Malad, INSERM,U423, F-75743 Paris, France
[3] Univ Rene Descartes, Hop Necker Enfants Malad, Serv Nephrol Pediat, F-75743 Paris, France
[4] Hop Robert Debre, INSERM, U458, F-75019 Paris, France
[5] Hop Robert Debre, Biochim Genet Lab, F-75019 Paris, France
[6] Hop Robert Debre, Lab Anatopathol, F-75019 Paris, France
[7] Hop Robert Debre, Serv Nephrol Pediat, F-75019 Paris, France
关键词
D O I
10.1086/301806
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Constitutional mutations of the WT1 gene, encoding a zinc-finger transcription factor involved in renal and gonadal development, are found in most patients with Denys-Drash syndrome (DDS), or diffuse mesangial sclerosis (DMS) associated with pseudohermaphroditism and/or Wilms tumor (WT). Most mutations in DDS patients lie in exon 8 or exon 9, encoding zinc finger 2 or zinc finger 3, respectively, with a hot spot (R394W) in exon 9. We analyzed a series of 24 patients, 10 with isolated DMS (IDMS), 10 with DDS, and 4 with urogenital abnormalities and/or WT. We report WT1 heterozygous mutations in 16 patients, 4 of whom presented with IDMS. One male and two female IDMS patients with WT1 mutations underwent normal puberty. Two mutations associated with IDMS are different from those described in DDS patients. No WT1 mutations were detected in the six other IDMS patients, suggesting genetic heterogeneity of this disease. We analyzed genotype/phenotype correlations, on the basis of the constitution of a WT1 mutation database of 84 germline mutations, to compare the distribution and type of mutations, according to the different symptoms. This demonstrated (1) the association between mutations in exons 8 and 9 and DMS; (2) among patients with DMS, a higher frequency of exon 8 mutations among 46,XY patients with female phenotype than among 46,XY patients with sexual ambiguity or male phenotype; and (3) statistically significant evidence that mutations in exons 8 and 9 preferentially affect amino acids with different functions.
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页码:824 / 833
页数:10
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