Eight novel variants in the SLC34A2 gene in pulmonary alveolar microlithiasis

Abstract

BackgroundPulmonary alveolar microlithiasis (PAM) is caused by genetic variants in the SLC34A2 gene, which encodes the sodium-dependent phosphate transport protein 2B (NaPi-2b). PAM is characterised by deposition of calcium phosphate concretions (microliths) in the alveoli leading to pulmonary dysfunction. The variant spectrum of SLC34A2 has not been well investigated and it is not yet known whether a genotype–phenotype correlation exists.MethodsWe collected DNA from 14 patients with PAM and four relatives, and analysed the coding regions of SLC34A2 by direct DNA sequencing. To determine the phenotype characteristics, clinical data were collected and a severity score was created for each variant, based on type and localisation within the protein.ResultsWe identified eight novel allelic variants of SLC34A2 in 14 patients with PAM. Four of these were nonsense variants, three were missense and one was a splice site variant. One patient was heterozygous for two different variants and all other patients were homozygous. Four patients were asymptomatic and 10 patients were symptomatic. The severity of the disease was associated with the variant severity.ConclusionsOur findings support a significant role for SLC34A2 in PAM and expand the variant spectrum of the disease. Thus, SLC34A2 variants were detected in all patients and eight novel allelic variants were discovered. An association between disease severity and the severity of the variants was found; however, this needs to be investigated in larger patient populations.

Pulmonary alveolar microlithiasis: no longer in the stone age

“…In a recent report, 12 unrelated patients from several European countries and the United States have been reported with 10 different allelic variants in the SLC34A2 gene. In addition, in a Turkish report, seven unrelated PAM patients were found with six different SLC34A2 variants [18,19]. In one of the patients, variants were present in a compound heterozygous state, whereas a homozygous-variant state was reported in the rest of the patients [18,19].…”

“…In addition, the variant c.1402_1404delACC in exon 12 has so far only been reported in patients from Europe [18]. In a recent published cohort of patients, a correlation between phenotype and genotype severity was found [18]. However, it still remains to be investigated whether a genotype-phenotype correlation exists in PAM.…”

“…To date, 30 different SLC34A2 variants in PAM have been reported in the literature and are located in most parts of the coding regions of the gene [18]. Variants include one or a few nucleotides or deletions involving either a single exon or several exons (table 1).…”

“…Some authors have pointed out the relationship between the geographical origin and the variant localisation, with patients from China and Japan reported with variants in exon 8 [39]. In addition, the variant c.1402_1404delACC in exon 12 has so far only been reported in patients from Europe [18]. In a recent published cohort of patients, a correlation between phenotype and genotype severity was found [18].…”

“…Several patients have reported extrapulmonary calcifications such as medullary nephrolithiasis, calcifications in the lumbar sympathetic chain, prostate, aorta and mitral valves, pericardium, the gastric wall, testicles, punctuate calcifications in seminal vesicles and periurethral and epididymal calcifications [6,18]. The extrapulmonary calcifications can cause symptoms in PAM such as infertility, haematuria and gallstone symptoms.…”