title: 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.
authors.affiliation: 1] Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden [2] Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Cilla
authors.initials: C
authors.lastname: Söderhäll
authors.affiliation: 1] Department of Women's and Children's Health, Center for Molecular Medicine, Karolinska Institutet CMM 02, Karolinska University Hospital, Stockholm, Sweden [2] Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Izabella Baranowska
authors.initials: IB
authors.lastname: Körberg
authors.affiliation: Department of Women's and Children's Health, Center for Molecular Medicine, Karolinska Institutet CMM 02, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Hanh T T
authors.initials: HT
authors.lastname: Thai
authors.affiliation: Department of Women's and Children's Health, Center for Molecular Medicine, Karolinska Institutet CMM 02, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Jia
authors.initials: J
authors.lastname: Cao
authors.affiliation: Department of Women's and Children's Health, Center for Molecular Medicine, Karolinska Institutet CMM 02, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Yougen
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Women's and Children's Health, Center for Molecular Medicine, Karolinska Institutet CMM 02, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Xufeng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Women's and Children's Health, Center for Molecular Medicine, Karolinska Institutet CMM 02, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Zu
authors.initials: Z
authors.lastname: Shulu
authors.affiliation: Department for Health Evidence, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Loes F M
authors.initials: LF
authors.lastname: van der Zanden
authors.affiliation: Department for Health Evidence, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Iris A L M
authors.initials: IA
authors.lastname: van Rooij
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Louise
authors.initials: L
authors.lastname: Frisén
authors.affiliation: 1] Department for Health Evidence, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands [2] Department of Pediatrics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Nel
authors.initials: N
authors.lastname: Roeleveld
authors.affiliation: Department of Women's and Children's Health, Center for Molecular Medicine, Karolinska Institutet CMM 02, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ellen
authors.initials: E
authors.lastname: Markljung
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kockum
authors.affiliation: 1] Department of Women's and Children's Health, Center for Molecular Medicine, Karolinska Institutet CMM 02, Karolinska University Hospital, Stockholm, Sweden [2] Department of Pediatric Surgery, Astrid Lindgren Children Hospital, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordenskjöld
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics; D000074425:Aldo-Keto Reductase Family 1 Member C3; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D005091:Exons; D005786:Gene Expression Regulation; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics; D007021:Hypospadias / Q000235:genetics*; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D010088:Oxidoreductases / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics; D044465:White People / Q000235:genetics; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
chemical_list: D015096:3-Hydroxysteroid Dehydrogenases; D000074425:Aldo-Keto Reductase Family 1 Member C3; D006911:Hydroxyprostaglandin Dehydrogenases; D006913:Hydroxysteroid Dehydrogenases; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D010088:Oxidoreductases; D011518:Proto-Oncogene Proteins; C105465:KLF6 protein, human; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); C487341:AKR1C3 protein, human; C048338:trans-1,2-dihydrobenzene-1,2-diol dehydrogenase