Universität zu Köln

Stange, Katja ORCID: 0000-0002-8416-2204, Desir, Julie, Kakar, Naseebullah, Mueller, Thomas D., Budde, Birgit S., Gordon, Christopher T., Horn, Denise, Seemann, Petra ORCID: 0000-0002-6056-6669 and Borck, Guntram (2015). A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia. Orphanet J. Rare Dis., 10. LONDON: BIOMED CENTRAL LTD. ISSN 1750-1172

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Abstract

Background: Grebe dysplasia, Hunter-Thompson dysplasia, and du Pan dysplasia constitute a spectrum of skeletal dysplasias inherited as an autosomal recessive trait characterized by short stature, severe acromesomelic shortening of the limbs, and normal axial skeleton. The majority of patients with these disorders have biallelic loss-of-function mutations of GDF5. In single instances, Grebe dysplasia and a Grebe dysplasia-like phenotype with genital anomalies have been shown to be caused by mutations in BMPR1B, encoding a GDF5 receptor. Methods: We clinically and radiologically characterised an acromesomelic chondrodysplasia in an adult woman born to consanguineous parents. We sequenced GDF5 and BMPR1B on DNA of the proposita. We performed 3D structural analysis and luciferase reporter assays to functionally investigate the identified BMPR1B mutation. Results: We extend the genotype-phenotype correlation in the acromesomelic chondrodysplasias by showing that the milder du Pan dysplasia can be caused by a hypomorphic BMPR1B mutation. We show that the homozygous c.91C>T, p.(Arg31Cys) mutation causing du Pan dysplasia leads to a significant loss of BMPR1B function, but to a lesser extent than the previously reported p.Cys53Arg mutation that results in the more severe Grebe dysplasia. Conclusions: The phenotypic severity gradient of the clinically and radiologically related acromesomelic chondrodysplasia spectrum of skeletal disorders may be due to the extent of functional impairment of the ligand-receptor pair GDF5-BMPR1B.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Stange, Katja UNSPECIFIED orcid.org/0000-0002-8416-2204 UNSPECIFIED Desir, Julie UNSPECIFIED UNSPECIFIED UNSPECIFIED Kakar, Naseebullah UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Thomas D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Budde, Birgit S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gordon, Christopher T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Horn, Denise UNSPECIFIED UNSPECIFIED UNSPECIFIED Seemann, Petra UNSPECIFIED orcid.org/0000-0002-6056-6669 UNSPECIFIED Borck, Guntram UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-400908
DOI:	10.1186/s13023-015-0299-5
Journal or Publication Title:	Orphanet J. Rare Dis.
Volume:	10
Date:	2015
Publisher:	BIOMED CENTRAL LTD
Place of Publication:	LONDON
ISSN:	1750-1172
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PROTEIN-1 CDMP1 GENE; LINKAGE ANALYSIS; CHONDRODYSPLASIA; GREBE; SPECIFICITY; MISSENSE; TOOL Multiple languages Genetics & Heredity; Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/40090