Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta.

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).

• Authors: Lutz Garbes, Kyungho Kim, Angelika Rieß, Heike Hoyer-Kuhn, Filippo Beleggia, Andrea Bevot, Mi Jeong Kim, Yang Hoon Huh, Hee-Seok Kweon, Ravi Savarirayan, David Amor, Purvi M Kakadia, Tobias Lindig, Karl Oliver Kagan, Jutta Becker, Simeon A Boyadjiev, Bernd Wollnik, Oliver Semler, Stefan K Bohlander, Jinoh Kim, Christian Netzer
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 96 Issue 3 Pg. 432-9 (Mar 05 2015) ISSN: 1537-6605 [Electronic] United States
• PMID: 25683121 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• SEC24D protein, human
• Vesicular Transport Proteins

Topics

• Alleles
• Animals
• Bone and Bones (pathology)
• Child
• Craniosynostoses (genetics)
• Endoplasmic Reticulum (metabolism)
• Eye Abnormalities (genetics)
• Female
• Heterozygote
• Humans
• Hydrocephalus (genetics)
• Male
• Mutation, Missense
• Osteogenesis Imperfecta (genetics)
• Pedigree
• Phenotype
• Protein Conformation
• Sequence Analysis, DNA
• Vesicular Transport Proteins (genetics, metabolism)
• Zebrafish (genetics)