title: Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis.
abstract: Pulmonary alveolar microlithiasis (PAM) is a rare disease characterized by the deposition of calcium phosphate microliths throughout the lungs. We first identified a PAM locus by homozygosity mapping to 4p15, then identified, by a candidate-gene approach, the gene responsible for the disease as SLC34A2 (the type IIb sodium-phosphate cotransporter gene), which is involved in phosphate homeostasis in several organs. We identified six homozygous exonic mutations in the seven unrelated patients with PAM we studied. Three of the mutations were frameshifts, one was a chain termination, one was an amino acid substitution, and one was a deletion spanning the minimal promoter and the first exon. Absence of functional protein product of the gene is compatible with calcium phosphate deposition in alveolar airspaces. We show that impaired activity of the phosphate transporter is presumably responsible for the microliths and that PAM is a recessive monogenic disease with full penetrance. Testicular microlithiasis (TM) is a disease that is more common than PAM. It is often associated with cancer and infertility. Since the gene we identified is also expressed in testis, we searched for mutations in subjects with TM. In 2 of the 15 subjects with TM we studied, we identified two rare variants, one synonymous and the other noncoding, that are possibly associated with the condition.
authors.affiliation: Department of Molecular Biology and Genetics, Boğaziçi University, Istanbul, Turkey.
authors.forename: Ayse
authors.initials: A
authors.lastname: Corut
authors.forename: Abdurrahman
authors.initials: A
authors.lastname: Senyigit
authors.forename: Sibel Aylin
authors.initials: SA
authors.lastname: Ugur
authors.forename: Sedat
authors.initials: S
authors.lastname: Altin
authors.forename: Ugur
authors.initials: U
authors.lastname: Ozcelik
authors.forename: Haluk
authors.initials: H
authors.lastname: Calisir
authors.forename: Zeki
authors.initials: Z
authors.lastname: Yildirim
authors.forename: Ayhan
authors.initials: A
authors.lastname: Gocmen
authors.forename: Aslihan
authors.initials: A
authors.lastname: Tolun
mesh_terms: D002874:Chromosome Mapping; D002894:Chromosomes, Human, Pair 4; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D006801:Humans; D020347:Lithiasis / Q000235:genetics*; D008171:Lung Diseases / Q000150:complications / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D010375:Pedigree; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb / Q000235:genetics*; D013733:Testicular Diseases / Q000150:complications / Q000235:genetics*
chemical_list: C493557:SLC34A2 protein, human; D050614:Sodium-Phosphate Cotransporter Proteins, Type IIb