title: Characterization of a novel Alu-Alu recombination-mediated genomic deletion in the TCIRG1 gene in five osteopetrotic patients.
abstract: Human malignant autosomal recessive osteopetrosis (ARO) is a genetically heterogeneous disorder caused by reduced bone resorption by osteoclasts. Biallelic mutations in the TCIRG1 gene, encoding the a3 subunit of the vacuolar proton pump, are responsible for more than one half of ARO patients. However, a few patients with monoallelic mutations have been described, raising the possibility of a dominant-like TCIRG1-dependent osteopetrosis, of a digenic disease, or of peculiar mutations difficult to detect with standard methods. We describe here a novel genomic deletion in the TCIRG1 gene explaining why, in some patients, mutations in only one allele have previously been found. The analysis of a proband from a consanguineous Turkish family allowed us to define the deletion boundaries encompassing introns 10 and 13 and occurring within AluSx repeat sequences, suggesting Alu-mediated homologous recombination as a mechanism. An identical genomic deletion at the heterozygous level was found in four unrelated Italian families in whom only a single mutated allele has previously been found. TCIRG1 haplotype analysis in these five families suggests a possible common ancestral origin for this large deletion. In summary, we describe the identification of a novel genomic deletion in the TCIRG1 gene that is of clinical relevance, especially in prenatal diagnosis.
authors: Institute for Biomedical Technologies, National Research Council, Segrate, Italy.
authors: Alessandra
authors: A
authors: Pangrazio
authors: Maria Elena
authors: ME
authors: Caldana
authors: Cristina
authors: C
authors: Sobacchi
authors: Cristina
authors: C
authors: Panaroni
authors: Lucia
authors: L
authors: Susani
authors: Ercan
authors: E
authors: Mihci
authors: Maria Luigia
authors: ML
authors: Cavaliere
authors: Silvia
authors: S
authors: Giliani
authors: Anna
authors: A
authors: Villa
authors: Annalisa
authors: A
authors: Frattini
mesh_terms: D020087:Alu Elements; D001483:Base Sequence; D003241:Consanguinity; D005192:Family Health; D017353:Gene Deletion; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D007558:Italy; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010022:Osteopetrosis / Q000235:genetics*; D011995:Recombination, Genetic; D014421:Turkey; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics*
chemical_list: C472421:TCIRG1 protein, human; D025262:Vacuolar Proton-Translocating ATPases