OBJECTIVE: To determine whether HESX1 mutations are present in patients with idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS). DESIGN: Polymerase chain reaction-based DNA sequencing was performed on 217 well-characterized IHH/KS patients. Putative missense mutations were analyzed by sorting intolerant from tolerant (SIFT) and Clustal Ω. SETTING: Academic medical center. PATIENT(S): Two hundred seventeen patients with IHH/KS and 192 controls. INTERVENTION(S): Deoxyribonucleic acid was extracted from patients and controls; genotype/phenotype comparisons were made. MAIN OUTCOME MEASURE(S): Deoxyribonucleic acid sequence of HESX1, SIFT analysis, and ortholog alignment. RESULT(S): Two novel heterozygous missense mutations (p.H42Y and p.V75L) and previously reported heterozygous missense mutation p.Q6H in HESX1 were identified in 3 of 217 patients (1.4%). All were males with KS. Both p.Q6H and p.H42Y were predicted to be deleterious by SIFT, whereas p.V75L was conserved in 8 of 9 species. No other IHH/KS gene mutations were present. CONCLUSION(S): HESX1 mutations may cause KS in addition to more severe phenotypes. Our findings expand the phenotypic spectrum of HESX1 mutations in humans, thereby broadening its role in development.
OBJECTIVE: To determine whether HESX1 mutations are present in patients with idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS). DESIGN: Polymerase chain reaction-based DNA sequencing was performed on 217 well-characterized IHH/KSpatients. Putative missense mutations were analyzed by sorting intolerant from tolerant (SIFT) and Clustal Ω. SETTING: Academic medical center. PATIENT(S): Two hundred seventeen patients with IHH/KS and 192 controls. INTERVENTION(S): Deoxyribonucleic acid was extracted from patients and controls; genotype/phenotype comparisons were made. MAIN OUTCOME MEASURE(S): Deoxyribonucleic acid sequence of HESX1, SIFT analysis, and ortholog alignment. RESULT(S): Two novel heterozygous missense mutations (p.H42Y and p.V75L) and previously reported heterozygous missense mutation p.Q6H in HESX1 were identified in 3 of 217 patients (1.4%). All were males with KS. Both p.Q6H and p.H42Y were predicted to be deleterious by SIFT, whereas p.V75L was conserved in 8 of 9 species. No other IHH/KS gene mutations were present. CONCLUSION(S): HESX1 mutations may cause KS in addition to more severe phenotypes. Our findings expand the phenotypic spectrum of HESX1 mutations in humans, thereby broadening its role in development.
Authors: J S Dasen; J P Martinez Barbera; T S Herman; S O Connell; L Olson; B Ju; J Tollkuhn; S H Baek; D W Rose; M G Rosenfeld Journal: Genes Dev Date: 2001-12-01 Impact factor: 11.361
Authors: P Q Thomas; M T Dattani; J M Brickman; D McNay; G Warne; M Zacharin; F Cameron; J Hurst; K Woods; D Dunger; R Stanhope; S Forrest; I C Robinson; R S Beddington Journal: Hum Mol Genet Date: 2001-01-01 Impact factor: 6.150
Authors: Luciani R Carvalho; Kathryn S Woods; Berenice B Mendonca; Nathalie Marcal; Andrea L Zamparini; Stefano Stifani; Joshua M Brickman; Ivo J P Arnhold; Mehul T Dattani Journal: J Clin Invest Date: 2003-10 Impact factor: 14.808
Authors: J P Hardelin; J Levilliers; I del Castillo; M Cohen-Salmon; R Legouis; S Blanchard; S Compain; P Bouloux; J Kirk; C Moraine Journal: Proc Natl Acad Sci U S A Date: 1992-09-01 Impact factor: 11.205
Authors: J M Brickman; M Clements; R Tyrell; D McNay; K Woods; J Warner; A Stewart; R S Beddington; M Dattani Journal: Development Date: 2001-12 Impact factor: 6.868