title: 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: Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany; Center of Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Institute of Genetics, University of Cologne, 50931 Cologne, Germany.
authors: Lutz
authors: L
authors: Garbes
authors: Division of Genomic Medicine, Department of Pediatrics, University of California Davis Medical Center, Sacramento, CA 95817, USA.
authors: Kyungho
authors: K
authors: Kim
authors: Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany.
authors: Angelika
authors: A
authors: Rieß
authors: Children's Hospital, University of Cologne, 50931 Cologne, Germany.
authors: Heike
authors: H
authors: Hoyer-Kuhn
authors: Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany; Center of Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
authors: Filippo
authors: F
authors: Beleggia
authors: Department of Paediatric Neurology and Developmental Medicine, University Children's Hospital Tuebingen, 72076 Tuebingen, Germany.
authors: Andrea
authors: A
authors: Bevot
authors: Division of Electron Microscopy Research, Korea Basic Science Institute, 169-148 Gwahangno, Yuseong-gu, Daejeon 305-806, Korea.
authors: Mi Jeong
authors: MJ
authors: Kim
authors: Division of Electron Microscopy Research, Korea Basic Science Institute, 169-148 Gwahangno, Yuseong-gu, Daejeon 305-806, Korea.
authors: Yang Hoon
authors: YH
authors: Huh
authors: Division of Electron Microscopy Research, Korea Basic Science Institute, 169-148 Gwahangno, Yuseong-gu, Daejeon 305-806, Korea.
authors: Hee-Seok
authors: HS
authors: Kweon
authors: Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, and University of Melbourne, Parkville, VIC 3052, Australia.
authors: Ravi
authors: R
authors: Savarirayan
authors: Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, and University of Melbourne, Parkville, VIC 3052, Australia.
authors: David
authors: D
authors: Amor
authors: Department of Molecular Medicine and Pathology, The University of Auckland, Auckland 1142, New Zealand.
authors: Purvi M
authors: PM
authors: Kakadia
authors: Department of Diagnostic and Interventional Neuroradiology, University of Tuebingen, 72076 Tuebingen, Germany.
authors: Tobias
authors: T
authors: Lindig
authors: Department of Obstetrics and Gynaecology, University of Tuebingen, 72076 Tuebingen, Germany.
authors: Karl Oliver
authors: KO
authors: Kagan
authors: Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany.
authors: Jutta
authors: J
authors: Becker
authors: Division of Genomic Medicine, Department of Pediatrics, University of California Davis Medical Center, Sacramento, CA 95817, USA.
authors: Simeon A
authors: SA
authors: Boyadjiev
authors: Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany; Center of Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
authors: Bernd
authors: B
authors: Wollnik
authors: Children's Hospital, University of Cologne, 50931 Cologne, Germany.
authors: Oliver
authors: O
authors: Semler
authors: Department of Molecular Medicine and Pathology, The University of Auckland, Auckland 1142, New Zealand.
authors: Stefan K
authors: SK
authors: Bohlander
authors: Division of Genomic Medicine, Department of Pediatrics, University of California Davis Medical Center, Sacramento, CA 95817, USA. Electronic address: jinoh.kim@ucdmc.ucdavis.edu.
authors: Jinoh
authors: J
authors: Kim
authors: Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany. Electronic address: christian.netzer@uk-koeln.de.
authors: Christian
authors: C
authors: Netzer
mesh_terms: D000483:Alleles; D000818:Animals; D001842:Bone and Bones / Q000473:pathology; D002648:Child; D003398:Craniosynostoses / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D006849:Hydrocephalus / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D017422:Sequence Analysis, DNA; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics
chemical_list: C530641:SEC24D protein, human; D033921:Vesicular Transport Proteins