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.643G4A (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.

The Genetic and Environmental Factors Underlying Hypospadias

“…One mutation has been described in the AKR1C3 gene in hypospadias (table 2). In silico studies predicted this mutation to damage protein function or structure [Söderhäll et al, 2015]. HSD17B3 encodes testosterone 17β-dehydro genase 3, another enzyme required for conversion of androstenedione into testosterone.…”

Associations of TGFBR1 and TGFBR2 gene polymorphisms with the risk of hypospadias: a case–control study in a Chinese population

“…Hypospadias surgery has been widely used in the region of urogenital reconstructive surgery using various techniques; for example the two-stage repair is a favorable method for proximal hypospadias [ 4 ]. The multifarious etiology of hypospadias remains unknown but seems to be an integration of genetic susceptibility, environmental pollutants, a maternal diet lacking protein, placental insufficiency, the use of hormone-containing contraceptives post-conception, high maternal BMI, parental subfertility, and endocrine disruption [ 5 – 10 ]. Hence, it is urged to acquire a full-scale knowledge of genetic mutations in the development of hypospadias.…”

“…Three genes of the AKR1C subfamily ( AKR1C2, AKR1C3 , and AKR1C4 ) as well as the KLF6 gene were selected for mutation screening owing to their functioning in testosterone metabolism and expression in genital skin in hypospadias cases. These AKRs can convert potent sex hormones (androgens, estrogen, and progesterone) into their inactive metabolites by acting as 3-keto-, 17-keto-, and 20-ketosteroid reductases [ 10 ]. The male urethral development may be influenced by genistein through the means of alterations in pathways and disrupting genes in the mitogen-activated protein kinase (MAPK) and transforming growth factor-β (TGF-β) signaling pathways [ 12 ].…”

AGORA, a data‐ and biobank for birth defects and childhood cancer

“…Another study, focused on nongenetic risk factors in hypospadias subgroups, provided clear indications for etiologic heterogeneity of hypospadias (van Rooij et al, ). The AGORA samples from hypospadias patients have also been used as replication cohorts in studies by other research groups (Geller et al, ; Soderhall et al, ).…”