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.

• MeSH
• Alopecia genetics   pathology   MeSH
• Alternative Splicing genetics   MeSH
• Anodontia genetics   pathology   MeSH
• Optic Atrophies, Hereditary genetics   pathology   MeSH
• DNA Primers genetics   MeSH
• Extracellular Matrix genetics   metabolism   MeSH
• Fibroblasts MeSH
• Fluorescent Antibody Technique MeSH
• Gene Frequency MeSH
• Genetic Predisposition to Disease genetics   MeSH
• Homeostasis genetics   MeSH
• Humans MeSH
• Chromosomes, Human, Pair 2 genetics   MeSH
• Microfilament Proteins MeSH
• RNA Splice Sites genetics   MeSH
• Molecular Sequence Data MeSH
• Neoplasm Proteins genetics   MeSH
• Codon, Nonsense genetics   MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Growth Disorders genetics   pathology   MeSH
• Receptors, Cell Surface genetics   MeSH
• Pedigree MeSH
• Base Sequence MeSH
• Sequence Analysis, DNA MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• ANTXR1 protein, human MeSH Browser
• DNA Primers MeSH
• Microfilament Proteins MeSH
• RNA Splice Sites MeSH
• Neoplasm Proteins MeSH
• Codon, Nonsense MeSH
• Receptors, Cell Surface MeSH