Mutations in ANTXR1 Cause GAPO Syndrome

• Published in: American journal of human genetics Vol. 92; no. 5; pp. 792 - 799
• Main Authors: Stránecký, Viktor, Hoischen, Alexander, Hartmannová, Hana, Zaki, Maha S., Chaudhary, Amit, Zudaire, Enrique, Nosková, Lenka, Barešová, Veronika, Přistoupilová, Anna, Hodaňová, Kateřina, Sovová, Jana, Hůlková, Helena, Piherová, Lenka, Hehir-Kwa, Jayne Y., de Silva, Deepthi, Senanayake, Manouri P., Farrag, Sameh, Zeman, Jiří, Martásek, Pavel, Baxová, Alice, Afifi, Hanan H., St. Croix, Brad, Brunner, Han G., Temtamy, Samia, Kmoch, Stanislav
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02-05-2013; Cell Press; Elsevier
• Subjects: Alopecia - genetics; Alopecia - pathology; Alternative Splicing - genetics; Amino acids; Anodontia - genetics; Anodontia - pathology; Base Sequence; Chromosomes, Human, Pair 2 - genetics; Codon, Nonsense - genetics; DNA Primers - genetics; Extracellular Matrix - genetics; Extracellular Matrix - metabolism; Fibroblasts; Fluorescent Antibody Technique; Gene Frequency; Genetic Predisposition to Disease - genetics; Genetics; Genotype & phenotype; Growth Disorders - genetics; Growth Disorders - pathology; Homeostasis; Homeostasis - genetics; Humans; Male; Molecular Sequence Data; Mutation; Neoplasm Proteins - genetics; Optic Atrophies, Hereditary - genetics; Optic Atrophies, Hereditary - pathology; Pedigree; Receptors, Cell Surface - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA Splice Sites - genetics; Rodents; Sequence Analysis, DNA
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2013.03.023

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.