Hypospadias : Gene mapping and candidate gene studied

摘要: Hypospadias is a common congenital malformation in boys, characterized by incomplete fusion of the urethral folds, abnormal opening urethra and different degrees curvature penis. In Sweden, incidence hypospadias 1.14 per 300 male live-births according to annual Swedish Malformation Registry. considered be complex genetic disorder caused interplay between environmental factors additive effects multiple genes. Several observations suggest that are under influence. To identify disease genes disorders, two main strategies have been used. We performed whole genome screening for linkage families with additional cases also DNA sequencing candidate chromosomal loci involved pathogenesis hypospadias, genome-wide analysis three-generational family showing autosomal dominant inheritance was performed. Fifteen individuals, whereof seven affected, were genotyped within total 426 microsatellite markers genotyping results analyzed using parametric non-parametric analyses. The subsequent fine mapping gave maximum both (LOD score 2.71) (NPL 5.01) single-point analyses marker D7S640. A susceptibility haplotype shared all affected boys identified D7S2519 D7S2442, respectively. This finding suggests novel locus (25 cM) at chromosome 7q32.2q36.1 (Study I). previous scan familial we suggestive nine regions. extend this new included. displayed an increased LOD on 8q24.1 10p15 altogether 82 families. From region 10p15, sequenced AKR1C3 KLF6 possible roles during development. Sequencing showed one mutation (c.697A>G, p.A215T) gene (c.496T>C, p.P166S) gene. addition, three polymorphisms (rs3763676, rs12529 rs7741) 5 end AKR1C3gene significant association hypospadias. These findings indicate possibly function as risk II). pathways implicated genital development; those androgen pathway crucially important. Therefore receptor (AR) alpha reductase (SRD5A2) 38 isolated cases. One AR (p.Q798E) another SRD5A2 (p.K199S) detected. Interestingly, high frequency rare leucine allele V89L polymorphism found. has shown confer decreased activity enzyme, thus may factor confirmed 158 compared 96 controls III). MAMLD1 (CXorf6) first causing from 97 sporadic elucidate role mutation, p.Q529K, predicted affect splicing process, found boy severe variants, p.V432A p.531ins3Q, reported previously indicated study polymorphisms. Additionally, p.N589S (rs2073043) alter protein structure detected (p-value <0.05). combination alleles p.P286S (rs41313406) over represented among It these inherited together (T-G), increasing few mutations gene, (p.N589S) IV). LIST OF PUBLICATIONS I. Thai HT*, Soderhall C*, Lagerstedt K, Omrani MD, Frisen L, Lundin J, Kockum I, Nordenskjold A. 7q32.2-q36.1. Hum Genet. 2008 Sep;124(2):155-60. *Equal contribution II. HT, C, Chen Y, Shulu Z, Fine identifies genes: KLF6. manuscript III. Kalbasi M, valine 5-alpha-reductase confers reduced J Clin Endocrinol Metab. 2005 Dec;90(12):6695-8. IV. Y*, K , Shengtian MAMLD1-gene associated Submitted. contribution.