TY - JOUR
T1 - Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase HSD17B10 and the E3 Ubiquitin Ligase HUWE1 Are Associated with Mental Retardation
AU - Froyen, Guy
AU - Corbett, Mark
AU - Vandewalle, Joke
AU - Jarvela, Irma
AU - Lawrence, Owen
AU - Meldrum, Cliff
AU - Bauters, Marijke
AU - Govaerts, Karen
AU - Vandeleur, Lucianne
AU - Van Esch, Hilde
AU - Chelly, Jamel
AU - Sanlaville, Damien
AU - van Bokhoven, Hans
AU - Ropers, Hans Hilger
AU - Laumonnier, Frederic
AU - Ranieri, Enzo
AU - Schwartz, Charles E.
AU - Abidi, Fatima
AU - Tarpey, Patrick S.
AU - Futreal, P. Andrew
AU - Whibley, Annabel
AU - Raymond, F. Lucy
AU - Stratton, Michael R.
AU - Fryns, Jean Pierre
AU - Scott, Rodney
AU - Peippo, Maarit
AU - Sipponen, Marjatta
AU - Partington, Michael
AU - Mowat, David
AU - Field, Michael
AU - Hackett, Anna
AU - Marynen, Peter
AU - Turner, Gillian
AU - Gécz, Jozef
N1 - Funding Information:
The authors thank all families for their cooperation, Marleen Willems for help with cell culture, Erica Woollatt for chromosome preparation, Marie Shaw for X inactivation studies, and Janice Fletcher for advice on metabolic screening. M.B. is supported by the IWT (Instituut voor Innovatie door Technologie en Wetenschap), Flanders, Belgium. H.V.E. is a postdoctoral researcher of the Fund for Scientific Research-Flanders (FWO-Vlaanderen), Belgium. J.G. is supported by the Australian NH&MRC senior research fellowship 250340 and Program grant 400121. This study was also supported by the European Union grant QLG3-CT-2002-01810 (EuroMRX Consortium), the NIH grant NINDS (NS31564, USA), the Wellcome Trust (UK), the NIHCD grant HD26202, the Neurology Foundation (Helsinki, Finland) and, in part, the South Carolina Department of Disabilities and Special Needs (SCDDSN).
PY - 2008/2/8
Y1 - 2008/2/8
N2 - Submicroscopic copy-number imbalances contribute significantly to the genetic etiology of human disease. Here, we report a novel microduplication hot spot at Xp11.22 identified in six unrelated families with predominantly nonsyndromic XLMR. All duplications segregate with the disease, including the large families MRX17 and MRX31. The minimal, commonly duplicated region contains three genes: RIBC1, HSD17B10, and HUWE1. RIBC1 could be excluded on the basis of its absence of expression in the brain and because it escapes X inactivation in females. For the other genes, expression array and quantitative PCR analysis in patient cell lines compared to controls showed a significant upregulation of HSD17B10 and HUWE1 as well as several important genes in their molecular pathways. Loss-of-function mutations of HSD17B10 have previously been associated with progressive neurological disease and XLMR. The E3 ubiquitin ligase HUWE1 has been implicated in TP53-associated regulation of the neuronal cell cycle. Here, we also report segregating sequence changes of highly conserved residues in HUWE1 in three XLMR families; these changes are possibly associated with the phenotype. Our findings demonstrate that an increased gene dosage of HSD17B10, HUWE1, or both contribute to the etiology of XLMR and suggest that point mutations in HUWE1 are associated with this disease too.
AB - Submicroscopic copy-number imbalances contribute significantly to the genetic etiology of human disease. Here, we report a novel microduplication hot spot at Xp11.22 identified in six unrelated families with predominantly nonsyndromic XLMR. All duplications segregate with the disease, including the large families MRX17 and MRX31. The minimal, commonly duplicated region contains three genes: RIBC1, HSD17B10, and HUWE1. RIBC1 could be excluded on the basis of its absence of expression in the brain and because it escapes X inactivation in females. For the other genes, expression array and quantitative PCR analysis in patient cell lines compared to controls showed a significant upregulation of HSD17B10 and HUWE1 as well as several important genes in their molecular pathways. Loss-of-function mutations of HSD17B10 have previously been associated with progressive neurological disease and XLMR. The E3 ubiquitin ligase HUWE1 has been implicated in TP53-associated regulation of the neuronal cell cycle. Here, we also report segregating sequence changes of highly conserved residues in HUWE1 in three XLMR families; these changes are possibly associated with the phenotype. Our findings demonstrate that an increased gene dosage of HSD17B10, HUWE1, or both contribute to the etiology of XLMR and suggest that point mutations in HUWE1 are associated with this disease too.
UR - http://www.scopus.com/inward/record.url?scp=40749130484&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2007.11.002
DO - 10.1016/j.ajhg.2007.11.002
M3 - Article
C2 - 18252223
AN - SCOPUS:40749130484
SN - 0002-9297
VL - 82
SP - 432
EP - 443
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -