Universität zu Köln

Garbes, Lutz, Kim, Kyungho, Riess, Angelika, Hoyer-Kuhn, Heike, Beleggia, Filippo ORCID: 0000-0003-0234-7094, Bevot, Andrea, Kim, Mi Jeong, Huh, Yang Hoon, Kweon, Hee-Seok, Savarirayan, Ravi, Amor, David, Kakadia, Purvi M., Lindig, Tobias, Kagan, Karl Oliver, Becker, Jutta, Boyadjiev, Simeon A., Wollnik, Bernd, Semler, Oliver ORCID: 0000-0003-0029-7556, Bohlander, Stefan K., Kim, Jinoh ORCID: 0000-0003-2841-147X and Netzer, Christian (2015). Mutations in SEC24D, Encoding a Component of the COPII Machinery, Cause a Syndromic Form of Osteogenesis Imperfecta. Am. J. Hum. Genet., 96 (3). S. 432 - 440. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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Abstract

As a result of a whole-exome sequencing study, we report three mutant alleles in SEC24D, a gene encoding a component of the COPII complex involved in protein export from the ER: the truncating mutation c.613C>T (p.Gln205*) and the missense mutations c.3044C>T (p.Ser1015Phe, located in a cargo-binding pocket) and c.2933A>C (p.Gln978Pro, located in the gelsolin-like domain). Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles, with c.3044C>T being embedded in a 14 Mb founder haplotype shared by all three. The affected individuals were a 7-year-old boy with a phenotype most closely resembling Cole-Carpenter syndrome and two fetuses initially suspected to have a severe type of osteogenesis imperfecta. All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset. The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures. Electron and immunofluorescence microscopy of skin fibroblasts of this individual revealed that ER export of procollagen was inefficient and that ER tubules were dilated, faithfully reproducing the cellular phenotype of individuals with cranio-lentico-sutural dysplasia (CLSD). CLSD is caused by SEC23A mutations and displays a largely overlapping craniofacial phenotype, but it is not characterized by generalized bone fragility and presented with cataracts in the original family described. The cellular and morphological phenotypes we report are in concordance with the phenotypes described for the Sec24d-deficient fish mutants vbi (medaka) and bulldog (zebrafish).

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Garbes, Lutz UNSPECIFIED UNSPECIFIED UNSPECIFIED Kim, Kyungho UNSPECIFIED UNSPECIFIED UNSPECIFIED Riess, Angelika UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoyer-Kuhn, Heike UNSPECIFIED UNSPECIFIED UNSPECIFIED Beleggia, Filippo UNSPECIFIED orcid.org/0000-0003-0234-7094 UNSPECIFIED Bevot, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Kim, Mi Jeong UNSPECIFIED UNSPECIFIED UNSPECIFIED Huh, Yang Hoon UNSPECIFIED UNSPECIFIED UNSPECIFIED Kweon, Hee-Seok UNSPECIFIED UNSPECIFIED UNSPECIFIED Savarirayan, Ravi UNSPECIFIED UNSPECIFIED UNSPECIFIED Amor, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Kakadia, Purvi M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lindig, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Kagan, Karl Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Jutta UNSPECIFIED UNSPECIFIED UNSPECIFIED Boyadjiev, Simeon A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wollnik, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Semler, Oliver UNSPECIFIED orcid.org/0000-0003-0029-7556 UNSPECIFIED Bohlander, Stefan K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kim, Jinoh UNSPECIFIED orcid.org/0000-0003-2841-147X UNSPECIFIED Netzer, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-410000
DOI:	10.1016/j.ajhg.2015.01.002
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	96
Number:	3
Page Range:	S. 432 - 440
Date:	2015
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language AUTOSOMAL RECESSIVE SYNDROME; LENTICULO-SUTURAL DYSPLASIA; BONE; HYDROCEPHALUS; TRAFFICKING; PROCOLLAGEN; DISORDERS Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/41000