FGFR2, FGF8, FGF10 and BMP7 as candidate genes for hypospadias

Beleza-Meireles, Ana; Lundberg, Fredrik; Lagerstedt, Kristina; Zhou, Xiaolei; Omrani, Davood; Frisén, Louise; Nordenskjöld, Agneta

doi:10.1038/sj.ejhg.5201777

Cited by 74 publications

(59 citation statements)

References 20 publications

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“…In fact, recent human genetic studies indicated the possible involvement of Bmp7 and Fgf(s) in the development of hypospadias. 41,42 Epithelial differentiation during the UP formation of the embryonic external genitalia (GT) One of the fundamental characters of the GT development is to develop endodermal epithelia along with GT formation, initially as CM and later forming the UP, subsequently the tubular urethra in the male GT.…”

Section: Discussionmentioning

confidence: 99%

Abnormal urethra formation in mouse models of Split-hand/split-foot malformation type 1 and type 4

et al. 2007

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Urogenital birth defects are one of the common phenotypes observed in hereditary human disorders. In particular, limb malformations are often associated with urogenital developmental abnormalities, as the case for Hand -foot -genital syndrome displaying similar hypoplasia/agenesis of limbs and external genitalia. Split-hand/split-foot malformation (SHFM) is a syndromic limb disorder affecting the central rays of the autopod with median clefts of the hands and feet, missing central fingers and often fusion of the remaining ones. SHFM type 1 (SHFM1) is linked to genomic deletions or rearrangements, which includes the distal-less-related homeogenes DLX5 and DLX6 as well as DSS1. SHFM type 4 (SHFM4) is associated with mutations in p63, which encodes a p53-related transcription factor. To understand that SHFM is associated with urogenital birth defects, we performed gene expression analysis and gene knockout mouse model analyses. We show here that Dlx5, Dlx6, p63 and Bmp7, one of the p63 downstream candidate genes, are all expressed in the developing urethral plate (UP) and that targeted inactivation of these genes in the mouse results in UP defects leading to abnormal urethra formation. These results suggested that different set of transcription factors and growth factor genes play similar developmental functions during embryonic urethra formation. Human SHFM syndromes display multiple phenotypes with variations in addition to split hand foot limb phenotype. These results suggest that different genes associated with human SHFM could also be involved in the aetiogenesis of hypospadias pointing toward a common molecular origin of these congenital malformations.

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Section: Discussionmentioning

confidence: 99%

Abnormal urethra formation in mouse models of Split-hand/split-foot malformation type 1 and type 4

et al. 2007

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“…The FGF gene family, especially FGF10 [26], is also implicated in the development of external genitalia in mice [27]. In humans, polymorphisms of FGF8, FGF10 and FGFR2 may be associated with an increased risk of hypospadias [28].…”

Section: Is Related To Mutations Of Homeoboxa13 (Hoxa13) Hoxa13 Allomentioning

confidence: 99%

Hypospadias: Interactions between environment and genetics

Kalfa

Philibert

Baskin

et al. 2011

Molecular and Cellular Endocrinology

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“…This would be consistent with hypospadias being a highly heterogeneous condition subject to multiple genetic and environmental factors. Indeed, several candidate genes such as ATF3, FKBP52, FGFR2, FGF8, FGF10 , and BMP7 have been identified, and multiple susceptibility factors for hypospadias have been found in several genes such as ESR1, ESR2 , and SRD5A2 [3,4,5,6,7]. …”

Section: Introductionmentioning

confidence: 99%

<i>MAMLD1 (CXorf6):</i> A New Gene Involved in Hypospadias

Ogata¹,

Laporte²,

Fukami³

2009

Horm Res Paediatr

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MAMLD1 (mastermind-like domain containing 1), previously known as CXorf6 (chromosome X open reading frame 6), has been shown to be a causative gene for hypospadias. This is primarily based on the identification of nonsense mutations (E124X, Q197X, and R653X), which undergo nonsense-mediated mRNA decay, in patients with penoscrotal hypospadias. Subsequent studies have shown that (1) the mouse homolog is transiently expressed in fetal Sertoli and Leydig cells around the critical period of sex development; (2) transient knockdown of Mamld1 results in significantly reduced testosterone production in murine Leydig tumor cells; (3) MAMLD1 protein shares homology to mastermind-like 2 (MAML2) protein that functions as a co-activator in canonical Notch signaling; (4) MAMLD1 localizes to the nuclear bodies and transactivates the promoter activity of a non-canonical Notch target gene hairy/enhancer of split 3 (Hes3), rather than the canonical Notch target genes such as Hes1 and Hes5, without demonstrable DNA-binding capacity, and (5) MAMLD1 is regulated by steroidogenic factor 1. These findings suggest that the MAMLD1 mutations cause hypospadias primarily because of compromised testosterone production around the critical period of sex development, and provide useful information for the molecular network involved in fetal testosterone production.

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FGFR2, FGF8, FGF10 and BMP7 as candidate genes for hypospadias

Cited by 74 publications

References 20 publications

Abnormal urethra formation in mouse models of Split-hand/split-foot malformation type 1 and type 4

Abnormal urethra formation in mouse models of Split-hand/split-foot malformation type 1 and type 4

Hypospadias: Interactions between environment and genetics

<i>MAMLD1 (CXorf6):</i> A New Gene Involved in Hypospadias

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