Universität zu Köln

Kuechler, Alma, Altmueller, Janine, Nuernberg, Peter, Kotthoff, Stefan, Kubisch, Christian ORCID: 0000-0003-4220-0978 and Borck, Guntram (2015). Exome sequencing identifies a novel heterozygous TGFB3 mutation in a disorder overlapping with Marfan and Loeys-Dietz syndrome. Mol. Cell. Probes, 29 (5). S. 330 - 335. LONDON: ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD. ISSN 0890-8508

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Abstract

Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS) are clinically related autosomal dominant systemic connective tissue disorders. Although mutations in several genes of the TGF-beta signalling and related pathways have been identified in the past (e.g. FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2), there are still many individuals with marfanoid phenotypes in whom no causative mutations are identified. We performed whole exome sequencing in two of three affected individuals from a family with phenotypic features overlapping MFS and LDS. The two affected children and their affected father had tall stature, arachnodactyly, hyperextensible joints, hypertelorism, bifid uvula, but no cardiac involvement, aortic dilation or eye involvement. We detected a novel heterozygous mutation in TGFB3, c.898C>G, predicting the missense substitution p.Arg300Gly. Sanger sequencing confirmed the mutation and its segregation with the phenotype. The first two TGFB3 mutations were reported previously in two unrelated individuals with marfanoid features: one individual with growth retardation carried a heterozygous loss-of-function mutation (c.1226G>A; p.Cys409Tyr; Rienhoff et al., 2013), whereas a child with overgrowth carried a mutation in the same codon as the mutation identified in the three affected individuals reported here (c.899G>A; p.Arg300Gln; Matyas et al., 2014). The mutations at codon Arg300 presumably lead to increased TGF-beta signalling, suggesting that the short or tall stature seen in patients with TGFB3 mutations may result from opposing effects of mutations on TGF-beta signalling. Thus, we add a novel human TGFB3 mutation, contribute to the clinical delineation of the emerging connective tissue disorder tentatively called Rienhoff syndrome and compare the data with a very recent report (Bertoli-Avella et al., 2015) on TGFB3 mutations associated with aortic aneurysms or dissections. (C) 2015 Elsevier Ltd. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kuechler, Alma UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Kotthoff, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Kubisch, Christian UNSPECIFIED orcid.org/0000-0003-4220-0978 UNSPECIFIED Borck, Guntram UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-392193
DOI:	10.1016/j.mcp.2015.07.003
Journal or Publication Title:	Mol. Cell. Probes
Volume:	29
Number:	5
Page Range:	S. 330 - 335
Date:	2015
Publisher:	ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
Place of Publication:	LONDON
ISSN:	0890-8508
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DE-NOVO MUTATION; SYNDROME FEATURES; PEPTIDE DOMAIN; OVERGROWTH; DIAGNOSIS; PATIENT; PALATE Multiple languages Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/39219