TY - JOUR
T1 - Mutation analysis of INSL3 and GREAT/LGR8 genes in familial cryptorchidism
AU - Feng, Shu
AU - Cortessis, Victoria K.
AU - Hwang, Andrew
AU - Hardy, Brian
AU - Koh, Chester J.
AU - Bogatcheva, Natalia V.
AU - Agoulnik, Alexander I.
N1 - Funding Information:
This work was supported by National Institutes of Health grants R01 HD37067 and P01 HD36289, and grants from the March of Dimes Birth Defect Foundation, STOP!CANCER, and the Donald E. and Delia B. Baxter Foundation.
Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2004/11
Y1 - 2004/11
N2 - Male mice deficient in insulin-like 3 hormone (Insl3) or its receptor, Great/Lgr8, exhibit cryptorchidism. Recently, sequence analysis of the human INSL3 and GREAT genes identified several allelic variants. These include polymorphisms without apparent functional consequence and a few alleles encoding products with compromised function. However, loss-of-function alleles appear to be rare in human cryptorchidism. Most patients studied to date are presumed to have had sporadic cryptorchidism. We postulated that any genotypic variants predisposing to cryptorchidism would be more prevalent among patients with familial cryptorchidism. We isolated genomic DNA from 13 individuals with personal and family histories of cryptorchidism and used polymerase chain reaction to amplify all exons of both INSL3 and GREAT, as well as INSL3 proximal promoter sequence, including a putative SF-1 transcription factor binding site. We directly sequenced all 20 amplicons and compared them with the wild-type alleles. We detected two silent substitutions and one missense (A60T) substitution in exon 1 of INSL3 and two silent substitutions in exon 12 and one missense (I604V) substitution in exon 17 of GREAT, all previously described. We found that in vitro the I604V GREAT variant receptor responds to INSL3 stimulation similarly to the wild-type receptor. We found polymorphic alleles of INSL3 and GREAT, but no deleterious mutations among individuals with familial cryptorchidism. Thus, mutations in these two genes are responsible only for a small proportion of familial cryptorchidism.
AB - Male mice deficient in insulin-like 3 hormone (Insl3) or its receptor, Great/Lgr8, exhibit cryptorchidism. Recently, sequence analysis of the human INSL3 and GREAT genes identified several allelic variants. These include polymorphisms without apparent functional consequence and a few alleles encoding products with compromised function. However, loss-of-function alleles appear to be rare in human cryptorchidism. Most patients studied to date are presumed to have had sporadic cryptorchidism. We postulated that any genotypic variants predisposing to cryptorchidism would be more prevalent among patients with familial cryptorchidism. We isolated genomic DNA from 13 individuals with personal and family histories of cryptorchidism and used polymerase chain reaction to amplify all exons of both INSL3 and GREAT, as well as INSL3 proximal promoter sequence, including a putative SF-1 transcription factor binding site. We directly sequenced all 20 amplicons and compared them with the wild-type alleles. We detected two silent substitutions and one missense (A60T) substitution in exon 1 of INSL3 and two silent substitutions in exon 12 and one missense (I604V) substitution in exon 17 of GREAT, all previously described. We found that in vitro the I604V GREAT variant receptor responds to INSL3 stimulation similarly to the wild-type receptor. We found polymorphic alleles of INSL3 and GREAT, but no deleterious mutations among individuals with familial cryptorchidism. Thus, mutations in these two genes are responsible only for a small proportion of familial cryptorchidism.
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U2 - 10.1016/j.urology.2004.06.051
DO - 10.1016/j.urology.2004.06.051
M3 - Article
C2 - 15533513
AN - SCOPUS:7944227674
VL - 64
SP - 1032
EP - 1036
JO - Urology
JF - Urology
SN - 0090-4295
IS - 5
ER -