Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase HSD17B10 and the E3 Ubiquitin Ligase HUWE1 Are Associated with Mental Retardation

Guy Froyen, Mark Corbett, Joke Vandewalle, Irma Jarvela, Owen Lawrence, Cliff Meldrum, Marijke Bauters, Karen Govaerts, Lucianne Vandeleur, Hilde Van Esch, Jamel Chelly, Damien Sanlaville, Hans van Bokhoven, Hans Hilger Ropers, Frederic Laumonnier, Enzo Ranieri, Charles E. Schwartz, Fatima Abidi, Patrick S. Tarpey, P. Andrew Futreal & 14 others Annabel Whibley, F. Lucy Raymond, Michael R. Stratton, Jean Pierre Fryns, Rodney Scott, Maarit Peippo, Marjatta Sipponen, Michael Partington, David Mowat, Michael Field, Anna Hackett, Peter Marynen, Gillian Turner, Jozef Gécz

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

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.

LanguageEnglish
Pages432-443
Number of pages12
JournalAmerican Journal of Human Genetics
Volume82
Issue number2
DOIs
Publication statusPublished - 8 Feb 2008
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Froyen, Guy ; Corbett, Mark ; Vandewalle, Joke ; Jarvela, Irma ; Lawrence, Owen ; Meldrum, Cliff ; Bauters, Marijke ; Govaerts, Karen ; Vandeleur, Lucianne ; Van Esch, Hilde ; Chelly, Jamel ; Sanlaville, Damien ; van Bokhoven, Hans ; Ropers, Hans Hilger ; Laumonnier, Frederic ; Ranieri, Enzo ; Schwartz, Charles E. ; Abidi, Fatima ; Tarpey, Patrick S. ; Futreal, P. Andrew ; Whibley, Annabel ; Raymond, F. Lucy ; Stratton, Michael R. ; Fryns, Jean Pierre ; Scott, Rodney ; Peippo, Maarit ; Sipponen, Marjatta ; Partington, Michael ; Mowat, David ; Field, Michael ; Hackett, Anna ; Marynen, Peter ; Turner, Gillian ; Gécz, Jozef. / Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase HSD17B10 and the E3 Ubiquitin Ligase HUWE1 Are Associated with Mental Retardation. In: American Journal of Human Genetics. 2008 ; Vol. 82, No. 2. pp. 432-443.
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abstract = "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.",
author = "Guy Froyen and Mark Corbett and Joke Vandewalle and Irma Jarvela and Owen Lawrence and Cliff Meldrum and Marijke Bauters and Karen Govaerts and Lucianne Vandeleur and {Van Esch}, Hilde and Jamel Chelly and Damien Sanlaville and {van Bokhoven}, Hans and Ropers, {Hans Hilger} and Frederic Laumonnier and Enzo Ranieri and Schwartz, {Charles E.} and Fatima Abidi and Tarpey, {Patrick S.} and Futreal, {P. Andrew} and Annabel Whibley and Raymond, {F. Lucy} and Stratton, {Michael R.} and Fryns, {Jean Pierre} and Rodney Scott and Maarit Peippo and Marjatta Sipponen and Michael Partington and David Mowat and Michael Field and Anna Hackett and Peter Marynen and Gillian Turner and Jozef G{\'e}cz",
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Froyen, G, Corbett, M, Vandewalle, J, Jarvela, I, Lawrence, O, Meldrum, C, Bauters, M, Govaerts, K, Vandeleur, L, Van Esch, H, Chelly, J, Sanlaville, D, van Bokhoven, H, Ropers, HH, Laumonnier, F, Ranieri, E, Schwartz, CE, Abidi, F, Tarpey, PS, Futreal, PA, Whibley, A, Raymond, FL, Stratton, MR, Fryns, JP, Scott, R, Peippo, M, Sipponen, M, Partington, M, Mowat, D, Field, M, Hackett, A, Marynen, P, Turner, G & Gécz, J 2008, 'Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase HSD17B10 and the E3 Ubiquitin Ligase HUWE1 Are Associated with Mental Retardation', American Journal of Human Genetics, vol. 82, no. 2, pp. 432-443. https://doi.org/10.1016/j.ajhg.2007.11.002

Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase HSD17B10 and the E3 Ubiquitin Ligase HUWE1 Are Associated with Mental Retardation. / Froyen, Guy; Corbett, Mark; Vandewalle, Joke; Jarvela, Irma; Lawrence, Owen; Meldrum, Cliff; Bauters, Marijke; Govaerts, Karen; Vandeleur, Lucianne; Van Esch, Hilde; Chelly, Jamel; Sanlaville, Damien; van Bokhoven, Hans; Ropers, Hans Hilger; Laumonnier, Frederic; Ranieri, Enzo; Schwartz, Charles E.; Abidi, Fatima; Tarpey, Patrick S.; Futreal, P. Andrew; Whibley, Annabel; Raymond, F. Lucy; Stratton, Michael R.; Fryns, Jean Pierre; Scott, Rodney; Peippo, Maarit; Sipponen, Marjatta; Partington, Michael; Mowat, David; Field, Michael; Hackett, Anna; Marynen, Peter; Turner, Gillian; Gécz, Jozef.

In: American Journal of Human Genetics, Vol. 82, No. 2, 08.02.2008, p. 432-443.

Research output: Contribution to journalArticle

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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

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.

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