Abstract
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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Acknowledgements
Invaluable support from Liz Robertson is appreciated. We thank Drs Giorgio R Merlo, Alex Joyner, Hisayo Nishida, Mingjun Sun, Shigeaki Kato, Denis Duboule, Chi-Chung Hui, Gail Martin, John McLachlan, Anne M Moon, Sawako Fujikawa, Kenta Sumiyama, Yoshihiko Satoh and Yukiko Ogino for encouragement and helps. We express our appreciation to Shiho Kitagawa for her valuable assistance. This study was supported by a Grant-in-Aid for Scientific Research on Priority Areas; General promotion of Cancer research in Japan, by a Grant-in-Aid for Scientific Research on Priority Areas; Mechanisms of Sex Differentiation, by the Global COE Research Program and by a Grant for Child Health and Development (17-2) from the Ministry of Health, Labour and Welfare. GL is supported by the grant ‘GENDACTYL’ of the French Agence National pour la Recherche (ANR). OB is supported by the Telethon (Italy) grant GP0218Y01.
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Suzuki, K., Haraguchi, R., Ogata, T. et al. Abnormal urethra formation in mouse models of Split-hand/split-foot malformation type 1 and type 4. Eur J Hum Genet 16, 36–44 (2008). https://doi.org/10.1038/sj.ejhg.5201925
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DOI: https://doi.org/10.1038/sj.ejhg.5201925
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