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

• Published in: European journal of human genetics : EJHG 2015-04, Vol.23 (4), p.516-522
• Main Authors: Söderhäll, Cilla, Körberg, Izabella Baranowska, Thai, Hanh T T, Cao, Jia, Chen, Yougen, Zhang, Xufeng, Shulu, Zu, van der Zanden, Loes F M, van Rooij, Iris A L M, Frisén, Louise, Roeleveld, Nel, Markljung, Ellen, Kockum, Ingrid, Nordenskjöld, Agneta
• Format: Article
• Language: English
• Subjects: 3-Hydroxysteroid Dehydrogenases - genetics; Aldo-Keto Reductase Family 1 Member C3; Androgens; Asian Continental Ancestry Group - genetics; Boys; Case-Control Studies; Childrens health; Chromosome 10; Chromosome 8; Chromosome Mapping; Chromosomes, Human, Pair 10 - genetics; Chromosomes, Human, Pair 8 - genetics; Dehydrogenases; Environmental factors; European Continental Ancestry Group - genetics; Exons; Families & family life; Gene Expression Regulation; Gene Frequency; Gene mapping; Genes; Genetic Association Studies; Genetic Predisposition to Disease; Genetics; Genomes; Genotype; Genotyping Techniques; Hospitals; Humans; Hydroxyprostaglandin Dehydrogenases - genetics; Hydroxysteroid Dehydrogenases - genetics; Hypospadias - genetics; Kinases; Kruppel-Like Factor 6; Kruppel-Like Transcription Factors - genetics; Linkage analysis; Lod Score; Male; Medicin och hälsovetenskap; Medicine; Metabolism; Microsatellite Repeats; Mutation; Oxidoreductases - genetics; Penis; Polymorphism, Single Nucleotide; Prostate cancer; Protein structure; Proto-Oncogene Proteins - genetics; Regulatory sequences; Structure-function relationships
• ISSN: 1018-4813; 1476-5438; 1476-5438
• DOI: 10.1038/ejhg.2014.129

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.