title: Mutations in ANTXR1 cause GAPO syndrome.
abstract: The genetic cause of GAPO syndrome, a condition characterized by growth retardation, alopecia, pseudoanodontia, and progressive visual impairment, has not previously been identified. We studied four ethnically unrelated affected individuals and identified homozygous nonsense mutations (c.262C>T [p.Arg88*] and c.505C>T [p.Arg169*]) or splicing mutations (c.1435-12A>G [p.Gly479Phefs*119]) in ANTXR1, which encodes anthrax toxin receptor 1. The nonsense mutations predictably trigger nonsense-mediated mRNA decay, resulting in the loss of ANTXR1. The transcript with the splicing mutation theoretically encodes a truncated ANTXR1 containing a neopeptide composed of 118 unique amino acids in its C terminus. GAPO syndrome's major phenotypic features, which include dental abnormalities and the accumulation of extracellular matrix, recapitulate those found in Antxr1-mutant mice and point toward an underlying defect in extracellular-matrix regulation. Thus, we propose that mutations affecting ANTXR1 function are responsible for this disease's characteristic generalized defect in extracellular-matrix homeostasis.
authors.affiliation: Institute for Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, 120 00 Prague 2, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Stránecký
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Hana
authors.initials: H
authors.lastname: Hartmannová
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.forename: Amit
authors.initials: A
authors.lastname: Chaudhary
authors.forename: Enrique
authors.initials: E
authors.lastname: Zudaire
authors.forename: Lenka
authors.initials: L
authors.lastname: Nosková
authors.forename: Veronika
authors.initials: V
authors.lastname: Barešová
authors.forename: Anna
authors.initials: A
authors.lastname: Přistoupilová
authors.forename: Kateřina
authors.initials: K
authors.lastname: Hodaňová
authors.forename: Jana
authors.initials: J
authors.lastname: Sovová
authors.forename: Helena
authors.initials: H
authors.lastname: Hůlková
authors.forename: Lenka
authors.initials: L
authors.lastname: Piherová
authors.forename: Jayne Y
authors.initials: JY
authors.lastname: Hehir-Kwa
authors.forename: Deepthi
authors.initials: D
authors.lastname: de Silva
authors.forename: Manouri P
authors.initials: MP
authors.lastname: Senanayake
authors.forename: Sameh
authors.initials: S
authors.lastname: Farrag
authors.forename: Jiří
authors.initials: J
authors.lastname: Zeman
authors.forename: Pavel
authors.initials: P
authors.lastname: Martásek
authors.forename: Alice
authors.initials: A
authors.lastname: Baxová
authors.forename: Hanan H
authors.initials: HH
authors.lastname: Afifi
authors.forename: Brad
authors.initials: B
authors.lastname: St Croix
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Samia
authors.initials: S
authors.lastname: Temtamy
authors.forename: Stanislav
authors.initials: S
authors.lastname: Kmoch
mesh_terms: D000505:Alopecia / Q000235:genetics* / Q000473:pathology; D017398:Alternative Splicing / Q000235:genetics; D000848:Anodontia / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D018389:Codon, Nonsense / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts; D005455:Fluorescent Antibody Technique; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006130:Growth Disorders / Q000235:genetics* / Q000473:pathology; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D008297:Male; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics*; D015418:Optic Atrophies, Hereditary / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: C473287:ANTXR1 protein, human; D018389:Codon, Nonsense; D017931:DNA Primers; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D022821:RNA Splice Sites; D011956:Receptors, Cell Surface