Mutations in SEC24D, Encoding a Component of the COPII Machinery, Cause a Syndromic Form of Osteogenesis Imperfecta

被引:119
作者
Garbes, Lutz [1 ,2 ,3 ]
Kim, Kyungho [4 ]
Riess, Angelika [5 ]
Hoyer-Kuhn, Heike [6 ]
Beleggia, Filippo [1 ,2 ,7 ]
Bevot, Andrea [8 ]
Kim, Mi Jeong [9 ]
Huh, Yang Hoon [9 ]
Kweon, Hee-Seok [9 ]
Savarirayan, Ravi [10 ,11 ]
Amor, David [10 ,11 ]
Kakadia, Purvi M. [12 ]
Lindig, Tobias [13 ]
Kagan, Karl Oliver [14 ]
Becker, Jutta [1 ]
Boyadjiev, Simeon A. [4 ]
Wollnik, Bernd [1 ,2 ,7 ]
Semler, Oliver [6 ]
Bohlander, Stefan K. [12 ]
Kim, Jinoh [4 ]
Netzer, Christian [1 ]
机构
[1] Univ Cologne, Inst Human Genet, D-50931 Cologne, Germany
[2] Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany
[3] Univ Cologne, Inst Genet, D-50931 Cologne, Germany
[4] Univ Calif Davis, Med Ctr, Dept Pediat, Div Genom Med, Sacramento, CA 95817 USA
[5] Univ Tubingen, Inst Med Genet & Appl Genom, D-72076 Tubingen, Germany
[6] Univ Cologne, Childrens Hosp, D-50931 Cologne, Germany
[7] Univ Cologne, Cologne Excellence Cluster Cellular Stress Respon, D-50931 Cologne, Germany
[8] Univ Childrens Hosp Tuebingen, Dept Paediat Neurol & Dev Med, D-72076 Tubingen, Germany
[9] Korea Basic Sci Inst, Div Electron Microscopy Res, Taejon 305806, South Korea
[10] Murdoch Childrens Res Inst, Victorian Clin Genet Serv, Parkville, Vic 3052, Australia
[11] Univ Melbourne, Parkville, Vic 3052, Australia
[12] Univ Auckland, Dept Mol Med & Pathol, Auckland 1142, New Zealand
[13] Univ Tubingen, Dept Diagnost & Intervent Neuroradiol, D-72076 Tubingen, Germany
[14] Univ Tubingen, Dept Obstet & Gynaecol, D-72076 Tubingen, Germany
基金
新加坡国家研究基金会;
关键词
AUTOSOMAL RECESSIVE SYNDROME; LENTICULO-SUTURAL DYSPLASIA; BONE; HYDROCEPHALUS; TRAFFICKING; PROCOLLAGEN; DISORDERS;
D O I
10.1016/j.ajhg.2015.01.002
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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).
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收藏
页码:432 / 439
页数:8
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