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:
CreatorsEmailORCIDORCID Put Code
Garbes, LutzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, KyunghoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riess, AngelikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoyer-Kuhn, HeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beleggia, FilippoUNSPECIFIEDorcid.org/0000-0003-0234-7094UNSPECIFIED
Bevot, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, Mi JeongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huh, Yang HoonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kweon, Hee-SeokUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Savarirayan, RaviUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amor, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kakadia, Purvi M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindig, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kagan, Karl OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, JuttaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boyadjiev, Simeon A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Semler, OliverUNSPECIFIEDorcid.org/0000-0003-0029-7556UNSPECIFIED
Bohlander, Stefan K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kim, JinohUNSPECIFIEDorcid.org/0000-0003-2841-147XUNSPECIFIED
Netzer, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
AUTOSOMAL RECESSIVE SYNDROME; LENTICULO-SUTURAL DYSPLASIA; BONE; HYDROCEPHALUS; TRAFFICKING; PROCOLLAGEN; DISORDERSMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/41000

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