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).
| Original language | English (US) |
|---|---|
| Pages (from-to) | 432-439 |
| Number of pages | 8 |
| Journal | American Journal of Human Genetics |
| Volume | 96 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 5 2015 |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta. / Garbes, Lutz; Kim, Kyungho; Rieß, Angelika; Hoyer-Kuhn, Heike; Beleggia, Filippo; 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; Boyd, Simeon; Wollnik, Bernd; Semler, Oliver; Bohlander, Stefan K.; Kim, Jinoh; Netzer, Christian.
In: American Journal of Human Genetics, Vol. 96, No. 3, 05.03.2015, p. 432-439.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta
AU - Garbes, Lutz
AU - Kim, Kyungho
AU - Rieß, Angelika
AU - Hoyer-Kuhn, Heike
AU - Beleggia, Filippo
AU - Bevot, Andrea
AU - Kim, Mi Jeong
AU - Huh, Yang Hoon
AU - Kweon, Hee Seok
AU - Savarirayan, Ravi
AU - Amor, David
AU - Kakadia, Purvi M.
AU - Lindig, Tobias
AU - Kagan, Karl Oliver
AU - Becker, Jutta
AU - Boyd, Simeon
AU - Wollnik, Bernd
AU - Semler, Oliver
AU - Bohlander, Stefan K.
AU - Kim, Jinoh
AU - Netzer, Christian
PY - 2015/3/5
Y1 - 2015/3/5
N2 - 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).
AB - 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).
UR - http://www.scopus.com/inward/record.url?scp=84924259368&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84924259368&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2015.01.002
DO - 10.1016/j.ajhg.2015.01.002
M3 - Article
C2 - 25683121
AN - SCOPUS:84924259368
VL - 96
SP - 432
EP - 439
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 3
ER -