Novel (60%) and Recurrent (40%) Androgen Receptor Gene Mutations in a Series of 59 Patients with a 46,XY Disorder of Sex Development
Por:
Audi, L, Fernandez-Cancio, M, Carrascosa, A, Andaluz, P, Toran, N, Piro, C, Vilaro, E, Vicens-Calvet, E, Gussinye, M, Albisu, MA, Yeste, D, Clemente, M, de la Calle, IH, Del Campo, M, Vendrell, T, Blanco, A, Martinez-Mora, J, Granada, ML, Salinas, I, Forn, J, Calaf, J, Angerri, O, Martinez-Sopena, MJ, del Valle, J, Garcia, E, Gracia-Bouthelier, R, Lapunzina, P, Mayayo, E, Labarta, JI, Lledo, G, del Pozo, JS, Arroyo, J, Perez-Aytes, A, Beneyto, M, Segura, A, Borras, V, Gabau, E, Caimari, M, Rodriguez, A, Martinez-Aedo, MJ, Carrera, M, Castano, L, Andrade, M, de la Vega, JAB
Publicada:
1 abr 2010
Resumen:
Background: Androgen receptor (AR) gene mutations are the most frequent cause of 46, XY disorders of sex development (DSD) and are associated with a variety of phenotypes, ranging from phenotypic women [complete androgen insensitivity syndrome (CAIS)] to milder degrees of undervirilization (partial form or PAIS) or men with only infertility (mild form or MAIS).
Objective: The aim of the study was to characterize the contribution of the AR gene to the molecular cause of 46, XY DSD in a series of Spanish patients.
Setting: We studied a series of 133 index patients with 46, XY DSD in whom gonads were differentiated as testes, with phenotypes including varying degrees of undervirilization, and in whom the AR gene was the first candidate for a molecular analysis.
Methods: The AR gene was sequenced (exons 1 to 8 with intronic flanking regions) in all patients and in family members of 61% of AR-mutated gene patients.
Results: AR gene mutations were found in 59 individuals (44.4% of index patients), of whom 46 (78%) were CAIS and 13 (22%) PAIS. Fifty-seven different mutations were found: 21.0% located in exon 1, 15.8% in exons 2 and 3, 57.9% in exons 4-8, and 5.3% intronic. Twenty-three mutations (40.4%) had been previously described and 34 (59.6%) were novel.
Conclusions: AR gene mutation is the most frequent cause of 46, XY DSD, with a clearly higher frequency in the complete phenotype. Mutations spread along the whole coding sequence, including exon 1. This series shows that 60% of mutations detected during the period 2002-2009 were novel. (J Clin Endocrinol Metab 95: 1876-1888, 2010)
Filiaciones:
Audi, L:
Autonomous Univ Barcelona, CIBERER Ctr Biomed Res Network Rare Dis, Unidad Invest Endocrinol Pediat, Hosp Vall Hebron,Inst Recerca,Inst Salud Carlos I, Barcelona 08035, Spain
Fernandez-Cancio, M:
Autonomous Univ Barcelona, CIBERER Ctr Biomed Res Network Rare Dis, Unidad Invest Endocrinol Pediat, Hosp Vall Hebron,Inst Recerca,Inst Salud Carlos I, Barcelona 08035, Spain
Carrascosa, A:
Autonomous Univ Barcelona, CIBERER Ctr Biomed Res Network Rare Dis, Unidad Invest Endocrinol Pediat, Hosp Vall Hebron,Inst Recerca,Inst Salud Carlos I, Barcelona 08035, Spain
Andaluz, P:
Autonomous Univ Barcelona, CIBERER Ctr Biomed Res Network Rare Dis, Unidad Invest Endocrinol Pediat, Hosp Vall Hebron,Inst Recerca,Inst Salud Carlos I, Barcelona 08035, Spain
Toran, N:
Hosp Valle De Hebron, Dept Pathol, Barcelona 08035, Spain
Piro, C:
Hosp Valle De Hebron, Dept Pediat Surg, Barcelona 08035, Spain
Vilaro, E:
Autonomous Univ Barcelona, CIBERER Ctr Biomed Res Network Rare Dis, Unidad Invest Endocrinol Pediat, Hosp Vall Hebron,Inst Recerca,Inst Salud Carlos I, Barcelona 08035, Spain
Vicens-Calvet, E:
Autonomous Univ Barcelona, CIBERER Ctr Biomed Res Network Rare Dis, Unidad Invest Endocrinol Pediat, Hosp Vall Hebron,Inst Recerca,Inst Salud Carlos I, Barcelona 08035, Spain
Gussinye, M:
Autonomous Univ Barcelona, CIBERER Ctr Biomed Res Network Rare Dis, Unidad Invest Endocrinol Pediat, Hosp Vall Hebron,Inst Recerca,Inst Salud Carlos I, Barcelona 08035, Spain
Albisu, MA:
Autonomous Univ Barcelona, CIBERER Ctr Biomed Res Network Rare Dis, Unidad Invest Endocrinol Pediat, Hosp Vall Hebron,Inst Recerca,Inst Salud Carlos I, Barcelona 08035, Spain
Yeste, D:
Autonomous Univ Barcelona, CIBERER Ctr Biomed Res Network Rare Dis, Unidad Invest Endocrinol Pediat, Hosp Vall Hebron,Inst Recerca,Inst Salud Carlos I, Barcelona 08035, Spain
Clemente, M:
Autonomous Univ Barcelona, CIBERER Ctr Biomed Res Network Rare Dis, Unidad Invest Endocrinol Pediat, Hosp Vall Hebron,Inst Recerca,Inst Salud Carlos I, Barcelona 08035, Spain
de la Calle, IH:
Hosp Valle De Hebron, Dept Gynecol, Barcelona 08035, Spain
Del Campo, M:
Hosp Valle De Hebron, Dept Genet, Barcelona 08035, Spain
Vendrell, T:
Hosp Valle De Hebron, Dept Genet, Barcelona 08035, Spain
Blanco, A:
Hosp Badalona Germans Trias & Pujol, Dept Pediat Surg, Badalona 08916, Spain
Martinez-Mora, J:
Hosp Badalona Germans Trias & Pujol, Dept Pediat Surg, Badalona 08916, Spain
Granada, ML:
Hosp Badalona Germans Trias & Pujol, Dept Biochem, Badalona 08916, Spain
Salinas, I:
Hosp Badalona Germans Trias & Pujol, Dept Endocrinol, Badalona 08916, Spain
Forn, J:
Hosp Santa Creu & Sant Pau, Dept Pediat, Barcelona 08025, Spain
Calaf, J:
Hosp Santa Creu & Sant Pau, Dept Gynecol, Barcelona 08025, Spain
Angerri, O:
Fundacio Puigvert, Dept Urol, Barcelona 08025, Spain
Martinez-Sopena, MJ:
Hosp Clin, Dept Pediat, Valladolid 47003, Spain
del Valle, J:
Hosp Virgen Rocio, Dept Pediat Endocrinol, Seville 41013, Spain
Garcia, E:
Hosp Virgen Rocio, Dept Pediat Endocrinol, Seville 41013, Spain
Gracia-Bouthelier, R:
Hosp La Paz, Dept Pediat Endocrinol, Madrid 28046, Spain
Lapunzina, P:
Hosp La Paz, Dept Genet, Madrid 28046, Spain
Mayayo, E:
Hosp Infantil Miguel Servet, Dept Pediat Endocrinol, Zaragoza 50009, Spain
Labarta, JI:
Hosp Infantil Miguel Servet, Dept Pediat Endocrinol, Zaragoza 50009, Spain
Lledo, G:
Hosp 12 Octubre, Dept Pediat Endocrinol, E-28041 Madrid, Spain
del Pozo, JS:
Hosp 12 Octubre, Dept Pediat Endocrinol, E-28041 Madrid, Spain
Arroyo, J:
Complejo Hosp Caceres, Dept Pediat, Caceres 10003, Spain
Perez-Aytes, A:
Hosp Infantil La Fe, Dept Pediat, Valencia 46009, Spain
Beneyto, M:
Hosp La Fe, Dept Genet, E-46009 Valencia, Spain
Segura, A:
Hosp Gen Univ Alicante, Dept Urol, Alicante 03010, Spain
Borras, V:
Hosp Granollers, Dept Pediat, Granollers 08401, Spain
Gabau, E:
Corp Hosp Parc Tauli, Dept Genet, Sabadell 08208, Spain
Caimari, M:
Hosp Son Dureta, Dept Pediat, Palma de Mallorca 07014, Spain
Rodriguez, A:
Hosp Txagorritxu, Dept Pediat, Vitoria 01009, Spain
Martinez-Aedo, MJ:
Hosp Carlos Haya, Dept Pediat Endocrinol, Malaga 29001, Spain
Carrera, M:
CPC, Barcelona 08950, Spain
Castano, L:
Hosp Cruces, Inst Salud Carlos III, CIBERER, Res Inst, Bilbao 48903, Spain
Andrade, M:
Hosp Xeral CIES, Dept Biochem, Vigo 36204, Spain
de la Vega, JAB:
Hosp Virgen Macarena, Dept Pediat Endocrinol, Seville 41009, Spain
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