Eight novel variants in the SLC34A2 gene in pulmonary alveolar microlithiasis.

Autor:	Jönsson ÅLM; Dept of Biomedicine, Aarhus University, Aarhus, Denmark aasajoen@rm.dk., Bendstrup E; Dept of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark., Mogensen S; Dept of Biomedicine, Aarhus University, Aarhus, Denmark., Kopras EJ; Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, OH, USA., McCormack FX; Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, OH, USA., Campo I; Pneumology unit, IRCCS San Matteo Hospital Foundation, Pavia, Italy., Mariani F; Pneumology unit, IRCCS San Matteo Hospital Foundation, Pavia, Italy., Escribano-Montaner A; Pediatric Pneumology Unit, Clinic University Hospital, Dept of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain., Holm AM; Dept of Respiratory Medicine, Oslo University Hospital, Oslo, Norway., Martinez-Colls MDM; Dept of Pediatrics, University Hospital Germans Trias i Pujol, Badalona, Spain., Pintos-Morell G; Dept of Pediatrics, University Hospital Germans Trias i Pujol, Badalona, Spain.; Centre for Rare Diseases, University Hospital Vall d'Hebron, Barcelona, Spain.; Research Institute IGTP, CIBERER-GCV08, Universitat Autònoma de Barcelona, Barcelona, Spain., Taillé C; APHP, Hopital Bichat, DHU FIRE, Pulmonology Dept, Reference Center for Rare Pulmonary Diseases, Unité Inserm 1152, Université Paris Diderot, Paris, France., Crestani B; APHP, Hopital Bichat, DHU FIRE, Pulmonology Dept, Reference Center for Rare Pulmonary Diseases, Unité Inserm 1152, Université Paris Diderot, Paris, France., Hilberg O; Dept of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark.; Medical Dept, Vejle Hospital, Vejle, Denmark., Hvarregaard Christensen J; Dept of Biomedicine, Aarhus University, Aarhus, Denmark.; Shared senior authorship., Simonsen U; Dept of Biomedicine, Aarhus University, Aarhus, Denmark.; Shared senior authorship.
Jazyk:	angličtina
Zdroj:	The European respiratory journal [Eur Respir J] 2020 Feb 27; Vol. 55 (2). Date of Electronic Publication: 2020 Feb 27 (Print Publication: 2020).
DOI:	10.1183/13993003.00806-2019
Abstrakt:	Background: Pulmonary 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. 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 10 patients were symptomatic. The severity of the disease was associated with the variant severity. Conclusions: Our 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. Competing Interests: Conflict of interest: Å.L.M. Jönsson has nothing to disclose. Conflict of interest: E. Bendstrup has nothing to disclose. Conflict of interest: S. Mogensen has nothing to disclose. Conflict of interest: E.J. Kopras reports grants from the NHLBI (R01HL127455 and U54HL127672) during the conduct of the study. Conflict of interest: F.X. McCormack reports grants from the NIH during the conduct of the study. Conflict of interest: I. Campo has nothing to disclose. Conflict of interest: F. Mariani has nothing to disclose. Conflict of interest: A. Escribano-Montaner has nothing to disclose. Conflict of interest: A.M. Holm has nothing to disclose. Conflict of interest: M.M. Martinez-Colls has nothing to disclose. Conflict of interest: G. Pintos-Morell reports personal fees for lectures from Shire, honoraria for consultancy from Sanofi-Genzyme and Alexion, and personal fees for travel and consultancy from Kyowa-Kirin, outside the submitted work. Conflict of interest: C. Taillé has been an investigator in trials and received personal fees for consultancy and advisory board work from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi and Roche, received personal fees for consultancy and advisory board work from Teva and Genzyme, and has been an investigator in trials from Boehringer Ingelheim, outside the submitted work. Conflict of interest: B. Crestani reports personal fees for lectures and nonfinancial support for meeting attendance from AstraZeneca, grants, personal fees for lectures and nonfinancial support for meeting attendance from Boehringer Ingelheim and Roche, personal fees for lectures and consultancy, as well as nonfinancial support for meeting attendance from Sanofi, personal fees for advisory board work from Genzyme and grants from MedImmune, outside the submitted work. Conflict of interest: O. Hilberg has nothing to disclose. Conflict of interest: J. Hvarregaard Christensen has nothing to disclose. Conflict of interest: U. Simonsen has nothing to disclose. (Copyright ©ERS 2020.)
Databáze:	MEDLINE
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