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

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.

• Authors: S L Anderson, C Jalas, A Fedick, K F Reid, T O Carpenter, D Chirnomas, N R Treff, J Ekstein, B Y Rubin
• Journal: Clinical genetics (Clin Genet) Vol. 88 Issue 1 Pg. 74-9 (Jul 2015) ISSN: 1399-0004 [Electronic] Denmark
• PMID: 24989235 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• RNA Splice Sites
• TCIRG1 protein, human
• Vacuolar Proton-Translocating ATPases

Topics

• DNA Mutational Analysis
• Founder Effect
• Gene Frequency
• Humans
• Infant
• Introns
• Jews (genetics)
• Osteopetrosis (genetics)
• Point Mutation
• RNA Splice Sites (genetics)
• Vacuolar Proton-Translocating ATPases (genetics)