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Fine mapping analysis confirms and strengthens linkage of four chromosomal regions in familial hypospadias.


ABSTRACT: Hypospadias is a common male genital malformation and is regarded as a complex disease affected by multiple genetic as well as environmental factors. In a previous genome-wide scan for familial hypospadias, we reported suggestive linkage in nine chromosomal regions. We have extended this analysis by including new families and additional markers using non-parametric linkage. The fine mapping analysis displayed an increased LOD score on chromosome 8q24.1 and 10p15 in altogether 82 families. On chromosome 10p15, with the highest LOD score, we further studied AKR1C2, AKR1C3 and AKR1C4 involved in steroid metabolism, as well as KLF6 expressed in preputial tissue from hypospadias patients. Mutation analysis of the AKR1C3 gene showed a new mutation, c.643G>A (p.(Ala215Thr)), in a boy with penile hypospadias. This mutation is predicted to have an impact on protein function and structure and was not found in controls. Altogether, we homed in on four chromosomal regions likely to harbor genes for hypospadias. Future studies will aim for studying regulatory sequence variants in these regions.

SUBMITTER: Soderhall C 

PROVIDER: S-EPMC4666571 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Fine mapping analysis confirms and strengthens linkage of four chromosomal regions in familial hypospadias.

Söderhäll Cilla C   Körberg Izabella Baranowska IB   Thai Hanh T T HT   Cao Jia J   Chen Yougen Y   Zhang Xufeng X   Shulu Zu Z   van der Zanden Loes F M LF   van Rooij Iris A L M IA   Frisén Louise L   Roeleveld Nel N   Markljung Ellen E   Kockum Ingrid I   Nordenskjöld Agneta A  

European journal of human genetics : EJHG 20140702 4


Hypospadias is a common male genital malformation and is regarded as a complex disease affected by multiple genetic as well as environmental factors. In a previous genome-wide scan for familial hypospadias, we reported suggestive linkage in nine chromosomal regions. We have extended this analysis by including new families and additional markers using non-parametric linkage. The fine mapping analysis displayed an increased LOD score on chromosome 8q24.1 and 10p15 in altogether 82 families. On chr  ...[more]

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