Identification of the gene responsible for pulmonary alveolar microlithiasis and possibly associated with testicular microlithiasis

Abstract

In this study two inherited disorders, namely pulmonary alveolar microlithiasis (PAM) and testicular microlithiasis (TM), were studied. PAM is a rare autosomal disease characterized by the deposition of calcium phosphate microliths throughout the lungs. TM is a more common disorder that is thought to follow a complex pattern of inheritance often associated with infertility and cancer. Autozygosity (homozygosity) mapping was used to fine-map the disease gene responsible for PAM resulting from parental consanguinity in a large Anatolian family. Computer based parametric tests were applied to evaluate the linkage information obtained by autozygosity mapping and confirmed gene localization. Later, positional candidate gene approach assessed SLC34A2 or type IIb sodium-phosphate cotransporter as the gene responsible for PAM. In this study, SSCP assay was employed to screen SLC34A2 for disease causing mutations in PAM patients. A total of five homozygous exonic mutations were identified in six unrelated PAM patients showing that impaired activity of the phosphate transporter SLC34A2 is presumably responsible for the alveolar microliths. Since the gene is also expressed in testis, using SSCP and subsequent DNA sequencing analysis, mutations were searched in 15 TM subjects and two rare variants identified.