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  A homozygous HOXD13 missense mutation causes a severe form of synpolydactyly with metacarpal to carpal transformation.

Ibrahim, D., Tayebi, N., Knaus, A., Stiege, A. C., Sahebzamani, A., Hecht, J., et al. (2016). A homozygous HOXD13 missense mutation causes a severe form of synpolydactyly with metacarpal to carpal transformation. American Journal of Medical Genetics Part A, 170(3), 615-621. doi:10.1002/ajmg.a.37464.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-42FC-1 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-42FD-0
Genre: Journal Article

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Ibrahim_et_al-2016-American_Journal_of_Medical_Genetics_Part_A.pdf (Publisher version), 711KB
 
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2015
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Ó 2015 Wiley Periodicals, Inc.
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 Creators:
Ibrahim, Daniel1, 2, Author              
Tayebi, Naeimeh 1, 2, Author
Knaus, Alexej2, Author
Stiege, Asita Carola1, Author              
Sahebzamani, Afsaneh 3, Author
Hecht, Jochen1, 4, 5, Author              
Mundlos, Stefan1, 2, 3, 5, Author              
Spielmann, Malte1, 2, 3, Author              
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Institute for Medical Genetics and Human Genetics, Charité, Freie Universität Universitätsmedizin Berlin, Berlin, Germany, ou_persistent22              
3Department of Genetic Welfare Organization , Kerman Iran, ou_persistent22              
4Berlin-Brandenburg School for Regene rative Therapies (BSRT), Berlin, Germany, ou_persistent22              
5Berlin Brandenburg Center for Regenerative Therapies, Charité, Freie—Universität,Berlin Universitätsmedizin Berlin, Berlin, Germany, ou_persistent22              

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Free keywords: HOXD13; loss of function; synpolydactyly
 Abstract: Synpolydactyly (SPD) is a rare congenital limb disorder characterized by syndactyly between the third and fourth fingers and an additional digit in the syndactylous web. In most cases SPD is caused by heterozygous mutations in HOXD13 resulting in the expansion of a N-terminal polyalanine tract. If homozygous, the mutation results in severe shortening of all metacarpals and phalanges with a morphological transformation of metacarpals to carpals. Here, we describe a novel homozygous missense mutation in a family with unaffected consanguineous parents and severe brachydactyly and metacarpal-to-carpal transformation in the affected child. We performed whole exome sequencing on the index patient, followed by Sanger sequencing of parents and patient to investigate cosegregation. The DNA-binding ability of the mutant protein was tested with electrophoretic mobility shift assays. We demonstrate that the c.938C>G (p.313T>R) mutation in the DNA-binding domain of HOXD13 prevents binding to DNA in vitro. Our results show to our knowledge for the first time that a missense mutation in HOXD13 underlies severe brachydactyly with metacarpal-to-carpal transformation. The mutation is non-penetrant in heterozygous carriers. In conjunction with the literature we propose the possibility that the metacarpal-to-carpal transformation results from a homozygous loss of functional HOXD13 protein in humans in combination with an accumulation of non-functional HOXD13 that might be able to interact with other transcription factors in the developing limb.

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Language(s): eng - English
 Dates: 2015-05-062015-10-222015-11-182016-03-01
 Publication Status: Published in print
 Pages: 7
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1002/ajmg.a.37464
 Degree: -

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Title: American Journal of Medical Genetics Part A
Source Genre: Journal
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Publ. Info: Hoboken, N.J. : Wiley-Liss
Pages: 7 Volume / Issue: 170 (3) Sequence Number: - Start / End Page: 615 - 621 Identifier: ISSN: 1552-4825
CoNE: /journals/resource/954925476465