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Clin Genet. 2015 Jul;88(1):74-9. doi: 10.1111/cge.12448. Epub 2014 Jul 31.

A founder mutation in the TCIRG1 gene causes osteopetrosis in the Ashkenazi Jewish population.

Author information

1
Department of Biological Sciences, Fordham University, Bronx, NY, 10458, USA.
2
Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, NY, 11204, USA.
3
Department of Microbiology and Molecular Genetics, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA.
4
Yale University School of Medicine, Departments of Pediatrics (Endocrinology) and Orthopedics and Rehabilitation, New Haven, CT, 06520, USA.
5
Reproductive Medicine Associates of New Jersey, Department of Research, Morristown, NJ, 07960, USA.
6
Dor Yeshorim, The Committee for Prevention of Jewish Diseases, Brooklyn, NY, 11211, USA.

Abstract

Osteopetrosis is a rare and heterogeneous genetic disorder characterized by dense bone mass that is a consequence of defective osteoclast function and/or development. Autosomal recessive osteopetrosis (ARO) is the most severe form and is often fatal within the first years of life; early hematopoietic stem cell transplant (HSCT) remains the only curative treatment for ARO. The majority of the ARO-causing mutations are located in the TCIRG1 gene. We report here the identification and characterization of an A to T transversion in the fourth base of the intron 2 donor splice site (c.117+4A→T) in TCIRG1, a mutation not previously seen in the Ashkenazi Jewish (AJ) population. Analysis of a random sample of individuals of AJ descent revealed a carrier frequency of approximately 1 in 350. Genotyping of five loci adjacent to the c.117+4A→T-containing TCIRG1 allele revealed that the presence of this mutation in the AJ population is due to a single founder. The identification of this mutation will enable population carrier testing and will facilitate the identification and treatment of individuals homozygous for this mutation.

KEYWORDS:

Ashkenazi Jewish; TCIRG1; founder mutation; osteopetrosis

PMID:
24989235
DOI:
10.1111/cge.12448
[Indexed for MEDLINE]
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