TY - JOUR
T1 - Mutations in ANTXR1 cause GAPO syndrome
AU - Stránecký, Viktor
AU - Hoischen, Alexander
AU - Hartmannová, Hana
AU - Zaki, Maha S.
AU - Chaudhary, Amit
AU - Zudaire, Enrique
AU - Nosková, Lenka
AU - Barešová, Veronika
AU - Přistoupilová, Anna
AU - Hodaňová, Kateřina
AU - Sovová, Jana
AU - Hůlková, Helena
AU - Piherová, Lenka
AU - Hehir-Kwa, Jayne Y.
AU - De Silva, Deepthi
AU - Senanayake, Manouri P.
AU - Farrag, Sameh
AU - Zeman, Jiří
AU - Martásek, Pavel
AU - Baxová, Alice
AU - Afifi, Hanan H.
AU - St. Croix, Brad
AU - Brunner, Han G.
AU - Temtamy, Samia
AU - Kmoch, Stanislav
N1 - Funding Information:
This work was supported by Charles University institutional programs PRVOUK-P24/LF1/3, UNCE 204011, and SVV2012/ 2645; by the Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University (CZ.1.05/1.1.00/02.0109); by the European Regional Development Fund; by grant NT13116-4/2012 from the Ministry of Education and Ministry of Health of the Czech Republic; and by the intramural research program of the National Cancer Institute, National Institutes of Health, US Department of Health and Social Services. A.H. was supported by the Netherlands Organization for Health Research and Development (ZonMW 916-12-095). We thank clinical colleagues and families who contributed samples used in this study, as well as members of the Genomic Disorders Group Nijmegen for their technical support. A.C. and B.S.C. are coinventors of filed patents related to the development of ANTXR1 antibodies for cancer therapy.
PY - 2013/5/2
Y1 - 2013/5/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84877585862&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2013.03.023
DO - 10.1016/j.ajhg.2013.03.023
M3 - Article
C2 - 23602711
AN - SCOPUS:84877585862
SN - 0002-9297
VL - 92
SP - 792
EP - 799
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -