SLC34A2 – Pulmonary Alveolar Microlithiasis

Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive lung disease characterized by widespread deposition of calcium-phosphate microliths in the alveolar spaces, often with striking clinico-radiological dissociation. Patients typically present in the second to fourth decades with progressive dyspnea, dry cough and, in advanced stages, cor pulmonale and pulmonary hypertension. Diagnosis is suggested by a classical “sandstorm” appearance on chest imaging and confirmed by genetic testing or lung biopsy.

The causal gene was identified by homozygosity mapping to chromosome 4p15 and candidate sequencing of SLC34A2, encoding the type IIb sodium-phosphate cotransporter, with six distinct homozygous exonic mutations found in seven unrelated probands ([PMID:16960801]). Subsequent familial studies in consanguineous kindreds demonstrated recessive inheritance with homozygous frameshift variants segregating in three affected siblings ([PMID:20046000]). A systematic review reported 34 allelic variants in 68 genetically characterized patients, including nonsense, missense, frameshift and splice-site changes in the homozygous or compound heterozygous state ([PMID:37259144]).

Expansion of the variant spectrum includes novel truncating mutations and a recurrent exon 5 deletion co-localized with the SLC34A2-ROS1 somatic fusion hotspot ([PMID:30262706]). Notably, the recurrent nonsense variant c.910A>T (p.Lys304Ter) and an accompanying missense change c.1363T>C (p.Tyr455His) have been observed in compound heterozygous patients with severe phenotypes ([PMID:25606438]).

Functional assays in Xenopus oocytes confirmed loss of phosphate transport for key variants—c.910A>T (p.Lys304Ter), c.1328delT (p.Leu443ArgfsTer6) and c.1402_1404del (p.Thr468del)—consistent with a loss-of-function mechanism ([PMID:35443721]). Homology modeling based on bacterial Na⁺-dicarboxylate transporter structures delineated critical substrate-binding and ion-coordination residues, validating the predicted structural impact of patient variants ([PMID:24655502]).

A single report without detectable SLC34A2 mutations in a PAM patient with low FGF23 levels raises the possibility of locus heterogeneity or modifier genes in rare instances ([PMID:20960258]).

Collectively, these data support a Strong gene–disease association for biallelic SLC34A2 mutations in Pulmonary Alveolar Microlithiasis. Genetic testing should be used for definitive diagnosis, family counseling and early intervention. Lung transplantation remains the only curative therapy in end-stage PAM. Key Take-home: Biallelic loss-of-function SLC34A2 variants underlie recessive PAM via impaired phosphate transport.

References

• American journal of human genetics • 2006 • Mutations in SLC34A2 cause pulmonary alveolar microlithiasis and are possibly associated with testicular microlithiasis. PMID:16960801
• Internal medicine (Tokyo, Japan) • 2010 • A frame-shift mutation in the SLC34A2 gene in three patients with pulmonary alveolar microlithiasis in an inbred family. PMID:20046000
• Orphanet journal of rare diseases • 2023 • New insights in the genetic variant spectrum of SLC34A2 in pulmonary alveolar microlithiasis; a systematic review. PMID:37259144
• Journal of genetics • 2018 • Novel deletion of SLC34A2 in Chinese patients of PAM shares mutation hot spot with fusion gene SLC34A2-ROS1 in lung cancer. PMID:30262706
• Meta gene • 2014 • SLC34A2 gene compound heterozygous mutation identification in a patient with pulmonary alveolar microlithiasis and computational 3D protein structure prediction. PMID:25606438
• Human genomics • 2022 • Impaired phosphate transport in SLC34A2 variants in patients with pulmonary alveolar microlithiasis. PMID:35443721
• Biophysical journal • 2014 • Structural fold and binding sites of the human Na⁺-phosphate cotransporter NaPi-I PMID:24655502
• Endocrine • 2010 • Mutation analysis and serum FGF23 level in a patient with pulmonary alveolar microlithiasis. PMID:20960258

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