Universität zu Köln

Budde, Birgit S., Mizumoto, Shuji ORCID: 0000-0002-4641-1505, Kogawa, Ryo, Becker, Christian, Altmueller, Janine, Thiele, Holger, Rueschendorf, Franz, Toliat, Mohammad R., Kaleschke, Gerrit, Haemmerle, Johannes M., Hoaehne, Wolfgang, Sugahara, Kazuyuki, Nuernberg, Peter and Kennerknecht, Ingo (2015). Skeletal dysplasia in a consanguineous clan from the island of Nias/Indonesia is caused by a novel mutation in B3GAT3. Hum. Genet., 134 (7). S. 691 - 705. NEW YORK: SPRINGER. ISSN 1432-1203

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Abstract

We describe a large family with disproportionate short stature and bone dysplasia from Nias in which we observed differences in severity when comparing the phenotypes of affected individuals from two remote branches. We conducted a linkage scan in the more severely affected family branch and determined a critical interval of 4.7 cM on chromosome 11. Sequencing of the primary candidate gene TBX10 did not reveal a disease-causing variant. When performing whole exome sequencing we noticed a homozygous missense variant in B3GAT3, c.419C > T [p.(Pro140Leu)]. B3GAT3 encodes beta-1,3-glucuronyltransferase-I (GlcAT-I). GlcAT-I catalyzes an initial step of proteoglycan synthesis and the mutation p. (Pro140Leu) lies within the donor substrate-binding subdomain of the catalytic domain. In contrast to the previously published mutation in B3GAT3, c.830G > A [p.(Arg277Gln)], no heart phenotype could be detected in our family. Functional studies revealed a markedly reduced GlcAT-I activity in lymphoblastoid cells from patients when compared to matched controls. Moreover, relative numbers of glycosaminoglycan (GAG) side chains were decreased in patient cells. We found that Pro140Leu-mutant GlcAT-I cannot efficiently transfer GlcA to the linker region trisaccharide. This failure results in a partial deficiency of both chondroitin sulfate and heparan sulfate chains. Since the phenotype of the Nias patients differs from the Larsen-like syndrome described for patients with mutation p.(Arg277Gln), we suggest mutation B3GAT3:p.(Pro140Leu) to cause a different type of GAG linkeropathy showing no involvement of the heart.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Budde, Birgit S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mizumoto, Shuji UNSPECIFIED orcid.org/0000-0002-4641-1505 UNSPECIFIED Kogawa, Ryo UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Rueschendorf, Franz UNSPECIFIED UNSPECIFIED UNSPECIFIED Toliat, Mohammad R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaleschke, Gerrit UNSPECIFIED UNSPECIFIED UNSPECIFIED Haemmerle, Johannes M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoaehne, Wolfgang UNSPECIFIED UNSPECIFIED UNSPECIFIED Sugahara, Kazuyuki UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Kennerknecht, Ingo UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-400370
DOI:	10.1007/s00439-015-1549-2
Journal or Publication Title:	Hum. Genet.
Volume:	134
Number:	7
Page Range:	S. 691 - 705
Date:	2015
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1432-1203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PROTEIN LINKAGE REGION; HUMAN GLUCURONOSYLTRANSFERASE I; PROTEOGLYCAN CORE PROTEIN; SULFATED GLYCOSAMINOGLYCANS; CHONDROITIN SULFATE; MOLECULAR-CLONING; HEPARAN-SULFATE; BIOSYNTHESIS; EXPRESSION; FAMILY Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/40037