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.

Phosphate Transport Kinetics and Structure-Function Relationships of SLC34 and SLC20 Proteins

“…On the other hand, naturally occurring mutations in the NaPi-IIc gene have been linked to the rare P i -handling disease hereditary hypophosphatemic rickets with hypercalcuria (HHRH) (Bergwitz, Roslin et al 2006;LorenzDepiereux, Benet-Pages et al 2006). Mutations in the NaPi-IIb gene have been proposed to cause pulmonary alveolar microlithiasis and possibly linked to testicular microlithiasis (Corut, Senyigit et al 2006). In general, these mutations result in truncations and mistargeting to the plasma membrane rather than altered transport function of the protein itself.…”

A case of pulmonary alveolar microlithiasis associated with a homozygous 195 kb deletion encompassing the entire SLC34A2 gene

“…Only five different homozygous deletions and one deletion plus insertion mutation have been described so far 5, 7, 8. The previously reported deletions were three different single nucleotide deletions, one deletion of 186 nucleotides, and a 5.5 kb long deletion 5, 8. We describe the first homozygous whole gene deletion detected by SNP array.…”

Phosphate transporters of the SLC20 and SLC34 families

“…These findings have challenged the assumption of NaPi-IIa being the major P i -reabsorbing protein in the human kidney. For NaPi-IIb, several reports indicate that mutations of this transporter lead to alveolar and testicular microlithiasis ( (Corut et al, 2006), for review see (Miyamoto et al).…”