title: Cranio-lenticulo-sutural dysplasia is caused by a SEC23A mutation leading to abnormal endoplasmic-reticulum-to-Golgi trafficking.
abstract: Cranio-lenticulo-sutural dysplasia (CLSD) is an autosomal recessive syndrome characterized by late-closing fontanels, sutural cataracts, facial dysmorphisms and skeletal defects mapped to chromosome 14q13-q21 (ref. 1). Here we show, using a positional cloning approach, that an F382L amino acid substitution in SEC23A segregates with this syndrome. SEC23A is an essential component of the COPII-coated vesicles that transport secretory proteins from the endoplasmic reticulum to the Golgi complex. Electron microscopy and immunofluorescence show that there is gross dilatation of the endoplasmic reticulum in fibroblasts from individuals affected with CLSD. These cells also exhibit cytoplasmic mislocalization of SEC31. Cell-free vesicle budding assays show that the F382L substitution results in loss of SEC23A function. A phenotype reminiscent of CLSD is observed in zebrafish embryos injected with sec23a-blocking morpholinos. Our observations suggest that disrupted endoplasmic reticulum export of the secretory proteins required for normal morphogenesis accounts for CLSD.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. simeon.boyd@ucdmc.ucdavis.edu
authors.forename: Simeon A
authors.initials: SA
authors.lastname: Boyadjiev
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Fromme
authors.forename: Jin
authors.initials: J
authors.lastname: Ben
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Chong
authors.forename: Christopher
authors.initials: C
authors.lastname: Nauta
authors.forename: David J
authors.initials: DJ
authors.lastname: Hur
authors.forename: George
authors.initials: G
authors.lastname: Zhang
authors.forename: Susan
authors.initials: S
authors.lastname: Hamamoto
authors.forename: Randy
authors.initials: R
authors.lastname: Schekman
authors.forename: Mariella
authors.initials: M
authors.lastname: Ravazzola
authors.forename: Lelio
authors.initials: L
authors.lastname: Orci
authors.forename: Wafaa
authors.initials: W
authors.lastname: Eyaid
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D002386:Cataract / Q000235:genetics; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005147:Facial Bones / Q000002:abnormalities; D005260:Female; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D021381:Protein Transport / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C512739:SEC23A protein, human; D033921:Vesicular Transport Proteins; D029961:Zebrafish Proteins