Mutations in the SLC34A2 Gene Are Associated with Pulmonary Alveolar Microlithiasis

Departments of Respiratory Medicine, Pathology, and Chest Surgery, Saitama Medical University, Saitama, Japan.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 03/2007; 175(3):263-8. DOI: 10.1164/rccm.200609-1274OC
Source: PubMed


Pulmonary alveolar microlithiasis is an autosomal recessive disorder in which microliths are formed in the alveolar space.
To identify the responsible gene that causes pulmonary alveolar microlithiasis.
By means of a genomewide single-nucleotide polymorphism analysis using DNA from three patients, we have narrowed the region in which the candidate gene is located. From this region, we have identified a gene that has mutations in all patients with pulmonary alveolar microlithiasis.
We identified a candidate gene, SLC34A2, that encodes a type IIb sodium phosphate cotransporter and that is mutated in six of six patients investigated. SLC34A2 is specifically expressed in type II alveolar cells, and the mutations abolished the normal gene function.
Mutations in the SLC34A2 gene that abolish normal gene function cause pulmonary alveolar microlithiasis.

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    • "A Turkish family having 6 patients from different generations has been reported.[15] There was history of consanguineous marriage in 30% of the parents of Japanese patients, who did not suffer from PAM.[18] Transmission is restricted to siblings; parental consanguinity was present in several siblings, supporting an autosomal recessive inheritance.[319–21] Both horizontal accumulation of the patients in a family and the presence of consanguineous marriages in the parents suggest that PAM is an autosomal recessive disease with a high penetrance. "
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    ABSTRACT: Pulmonary alveolar microlithiasis (PAM) is a rare, chronic lung disease with bilateral intra-alveolar calcium and phosphate deposition throughout the lung parenchyma with predominance to lower and midzone. Although, etiology and pathogenesis of PAM is not fully understood, the mutation in SLC34A2 gene that encodes a sodium-phosphate co-transporter in alveolar type II cells resulting in the accumulation and forming of microliths rich in calcium phosphate (due to impaired clearance) are considered to be the cause of the disease. Chest radiograph and high-resolution CT of thorax are nearly pathognomonic for diagnosing PAM. HRCT demonstrates diffuse micronodules showing slight perilobular predominance resulting in calcification of interlobular septa. Patients with PAM are asymptomatic till development of hypoxemia and cor-pulmonale. No therapy has been proven to be beneficial except lung transplantation.
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    • "We confirmed the power of this algorithm using 6 patients with Siiyama-type α1-antitrypsin deficiency, a rare autosomal recessive disease in Japan [7,8]. The preliminary version of the algorithm described here has been used to prove that the SLC34A2 gene is responsible for pulmonary alveolar microlithiasis [9]; the current version has been used to show that the OPTN gene is responsible for amyotrophic lateral sclerosis [10]. "
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