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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    • "Mutations in human SFTPB (surfactant associated protein B), and ABCA3 (ATP-binding cassette, sub-family A (ABC1), member 3) genes cause severe lung disease in new-borns, often resulting in respiratory failure at birth [50], [51], [52]. Mutations in SLC34A2 (solute carrier family 34, member 2), a sodium phosphate co-transporter specifically expressed in type II alveolar cells, cause pulmonary alveolar microlithiasis [53]. Previous studies from this laboratory and others demonstrated that CEPBα is an important regulator of respiratory epithelial differentiation and is required for synthesis of surfactant lipids and proteins necessary for lung function at birth, deletion of the Cebpa gene in respiratory epithelial cells in the fetal mouse lung causing respiratory failure at birth [12]. "
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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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    ABSTRACT: Homozygosity mapping is a powerful procedure that is capable of detecting recessive disease-causing genes in a few patients from families with a history of inbreeding. We report here a homozygosity mapping algorithm for high-density single nucleotide polymorphism arrays that is able to (i) correct genotyping errors, (ii) search for autozygous segments genome-wide through regions with runs of homozygous SNPs, (iii) check the validity of the inbreeding history, and (iv) calculate the probability of the disease-causing gene being located in the regions identified. The genotyping error correction restored an average of 94.2% of the total length of all regions with run of homozygous SNPs, and 99.9% of the total length of them that were longer than 2 cM. At the end of the analysis, we would know the probability that regions identified contain a disease-causing gene, and we would be able to determine how much effort should be devoted to scrutinizing the regions. We confirmed the power of this algorithm using 6 patients with Siiyama-type α1-antitrypsin deficiency, a rare autosomal recessive disease in Japan. Our procedure will accelerate the identification of disease-causing genes using high-density SNP array data.
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