title: 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.affiliation: Department of Biological Sciences, Fordham University, Bronx, NY, 10458, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Anderson
authors.affiliation: Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, NY, 11204, USA.
authors.forename: C
authors.identifier: http://orcid.org/0000-0002-3788-0924
authors.initials: C
authors.lastname: Jalas
authors.affiliation: Department of Microbiology and Molecular Genetics, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA.
authors.forename: A
authors.initials: A
authors.lastname: Fedick
authors.affiliation: Department of Biological Sciences, Fordham University, Bronx, NY, 10458, USA.
authors.forename: K F
authors.initials: KF
authors.lastname: Reid
authors.affiliation: Yale University School of Medicine, Departments of Pediatrics (Endocrinology) and Orthopedics and Rehabilitation, New Haven, CT, 06520, USA.
authors.forename: T O
authors.initials: TO
authors.lastname: Carpenter
authors.affiliation: Yale University School of Medicine, Departments of Pediatrics (Endocrinology) and Orthopedics and Rehabilitation, New Haven, CT, 06520, USA.
authors.forename: D
authors.initials: D
authors.lastname: Chirnomas
authors.affiliation: Department of Microbiology and Molecular Genetics, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA.|Reproductive Medicine Associates of New Jersey, Department of Research, Morristown, NJ, 07960, USA.
authors.forename: N R
authors.initials: NR
authors.lastname: Treff
authors.affiliation: Dor Yeshorim, The Committee for Prevention of Jewish Diseases, Brooklyn, NY, 11211, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ekstein
authors.affiliation: Department of Biological Sciences, Fordham University, Bronx, NY, 10458, USA.
authors.forename: B Y
authors.initials: BY
authors.lastname: Rubin
mesh_terms: D004252:DNA Mutational Analysis; D018703:Founder Effect; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D007438:Introns; D007585:Jews / Q000235:genetics; D010022:Osteopetrosis / Q000235:genetics*; D017354:Point Mutation; D022821:RNA Splice Sites / Q000235:genetics*; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics*
chemical_list: D022821:RNA Splice Sites; C472421:TCIRG1 protein, human; D025262:Vacuolar Proton-Translocating ATPases
keywords: Ashkenazi Jewish; TCIRG1; founder mutation; osteopetrosis