title: Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation.
abstract: We observed two unrelated consanguineous families with malformation syndromes sharing anophthalmia and distinct eyebrows as common signs, but differing for alveolar capillary dysplasia or complex congenital heart defect in one and diaphragmatic hernia in the other family. Homozygosity mapping revealed linkage to a common locus on chromosome 15, and pathogenic homozygous mutations were identified in STRA6, a member of a large group of "stimulated by retinoic acid" genes encoding novel transmembrane proteins, transcription factors, and secreted signaling molecules or proteins of largely unknown function. Subsequently, homozygous STRA6 mutations were also demonstrated in 3 of 13 patients chosen on the basis of significant phenotypic overlap to the original cases. While a homozygous deletion generating a premature stop codon (p.G50AfsX22) led to absence of the immunoreactive protein in patient's fibroblast culture, structural analysis of three missense mutations (P90L, P293L, and T321P) suggested significant effects on the geometry of the loops connecting the transmembrane helices of STRA6. Two further variations in the C-terminus (T644M and R655C) alter specific functional sites, an SH2-binding motif and a phosphorylation site, respectively. STRA6 mutations thus define a pleiotropic malformation syndrome representing the first human phenotype associated with mutations in a gene from the "STRA" group.
authors.affiliation: Institute of Human Genetics, Friedrich Alexander University Erlangen Nuremberg, Erlangen, Germany.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pasutto
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hammersen
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: David R
authors.initials: DR
authors.lastname: Fitzpatrick
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Frank
authors.initials: F
authors.lastname: Brasch
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Schirmer-Zimmermann
authors.forename: John L
authors.initials: JL
authors.lastname: Tolmie
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.forename: Gunnar
authors.initials: G
authors.lastname: Houge
authors.forename: Lorena
authors.initials: L
authors.lastname: Fernández-Martínez
authors.forename: Sarah
authors.initials: S
authors.lastname: Keating
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.forename: Raoul C M
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Axel
authors.initials: A
authors.lastname: von der Wense
authors.forename: Anne
authors.initials: A
authors.lastname: Slavotinek
authors.forename: Peter
authors.initials: P
authors.lastname: Meinecke
authors.forename: Pierre
authors.initials: P
authors.lastname: Bitoun
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000853:Anophthalmos / Q000235:genetics; D002196:Capillaries / Q000002:abnormalities; D003241:Consanguinity; D005260:Female; D006330:Heart Defects, Congenital / Q000235:genetics; D006548:Hernia, Diaphragmatic / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics; D008168:Lung / Q000002:abnormalities* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010766:Phosphorylation; D011650:Pulmonary Alveoli / Q000098:blood supply; D011956:Receptors, Cell Surface / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: D008565:Membrane Proteins; D011956:Receptors, Cell Surface; C027928:retinol binding protein receptor