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).

MECHANISMS IN ENDOCRINOLOGY: Genetics of human bone formation

“…The disease was already described in 1987, but recently, whole-exome sequencing (WES) resulted in the identification of P4HB and SEC24D, both involved in collagen 1 biosynthesis, as disease-causing genes for AD and AR forms of Cole-Carpenter disease respectively ( Fig. 1 and Table 1) (40,41). These findings confirm the importance of collagen 1 metabolism in defining bone mass and bone strength.…”

Bone Material Properties in Osteogenesis Imperfecta

“…X-linked early-onset severe osteoporosis without other OI features (126) Mineralization regulation SERPINF1 Pigment epithelium-derived factor Yes Slowly progressively worsening OI; osteoid mineralization defect (no endochondral defect) ( (133) Linker enzyme deficiency XYLT2 Xylosyltransferase II ? Vertebral fractures, cataracts, heart defects (134) The noncollagenous proteins within bone have been suggested to have a range of functions, from the formation of collagen fibrils and initiation of mineral platelet formation, to mineral maturation and collagen cross-linking.…”

Molecular Consequences of the SERPINH1/HSP47 Mutation in the Dachshund Natural Model of Osteogenesis Imperfecta

“…Over the last 8 years, mutations in several noncollagenous genes involved in the post-translational processing of procollagen I, in osteoblast-specific signaling, or in gene regulation have been characterized in either dominant or recessive forms of OI: CRTAP (OMIM 605497), LEPRE1 (OMIM 610339), PPIB (OMIM 123841), PLOD2 (OMIM 601865), FKBP10 (OMIM 607063), BMP1 (OMIM 112264), CREB3L1 (Entrez ID 90993), IFITM5 (OMIM 614757), PLS3 (OMIM 300131), TMEM38B (OMIM 611236), WNT1 (OMIM 164820), SP7 (OMIM 606633), SERPINF1 (OMIM 172860), SERPINH1 (OMIM 600943) (2), and most recently, P4HB (OMIM 176790) (3) and SEC24D (OMIM 607186) (4).…”