TY - JOUR T1 - Eight novel variants in the <em>SLC34A2</em> gene in pulmonary alveolar microlithiasis JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.00806-2019 SP - 1900806 AU - Åsa Lina M. Jönsson AU - Elisabeth Bendstrup AU - Susie Mogensen AU - Elizabeth J. Kopras AU - Francis X. McCormack AU - Ilaria Campo AU - Francesca Mariani AU - Amparo Escribano-Montaner AU - Are M. Holm AU - Maria del Mar Martinez-Colls AU - Guillem Pintos-Morell AU - Camille Taillé AU - Bruno Crestani AU - Ole Hilberg AU - Jane Hvarregaard Christensen AU - Ulf Simonsen Y1 - 2019/01/01 UR - http://erj.ersjournals.com/content/early/2019/11/19/13993003.00806-2019.abstract N2 - Background Pulmonary alveolar microlithiasis (PAM) is caused by genetic variants in the SLC34A2 gene, which encodes the sodium-dependent phosphate transport protein 2B. PAM is characterised by deposition of calcium-phosphate concretions in the alveoli leading to pulmonary dysfunction. The variant spectrum of SLC34A2 is not yet well investigated and it is not known whether a genotype-phenotype correlation exist.Methods We 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.Results We 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 ten patients were symptomatic. The severity of the disease was associated with the variant severity.Conclusions Our findings support a significant role of 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, but this needs to be investigated in larger patient populations.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Jönsson has nothing to disclose.Conflict of interest: Dr. Bendstrup has nothing to disclose.Conflict of interest: Dr. Mogensen has nothing to disclose.Conflict of interest: Ms. Kopras reports grants from NHLBI during the conduct of the study.Conflict of interest: Dr. McCormack reports grants from the National Institutes of Health during the conduct of the study.Conflict of interest: Dr. Campo has nothing to disclose.Conflict of interest: Dr. Mariani has nothing to disclose.Conflict of interest: Dr. Escribano-Montaner has nothing to disclose.Conflict of interest: Dr. Holm has nothing to disclose.Conflict of interest: Dr. Martinez-Colls has nothing to disclose.Conflict of interest: Dr. Pintos-Morell reports personal fees from Shire, other from Sanofi-Genzyme, personal fees from Alexion, personal fees from Kyowa-Kirin, outside the submitted work.Conflict of interest: Pr. Taillé reports other from GlaxoSmithKline, non-financial support from GlaxoSmithKline, during the conduct of the study; personal fees and other from AstraZeneca, personal fees from Teva, personal fees and other from GlaxoSmithKline, personal fees and other from Novartis, personal fees and other from Sanofi, personal fees from Genzyme, personal fees and other from Roche, other from Boehringer Ingelheim, outside the submitted work.Conflict of interest: Dr. Crestani reports personal fees and non-financial support from Astra-Zeneca, grants, personal fees and non-financial support from Boehringer Ingelheim, grants from MedImmune, grants, personal fees and non-financial support from Roche, personal fees and non-financial support from Sanofi, personal fees from Genzyme, outside the submitted work.Conflict of interest: Dr. Hilberg has nothing to disclose.Conflict of interest: Dr. Christensen has nothing to disclose.Conflict of interest: Dr. Simonsen has nothing to disclose. ER -