Abstract
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.
Abstract
Eight novel variants in the SLC34A2 gene have been identified in 14 patients with pulmonary alveolar microlithiasis (PAM), which emphasises the importance of the gene in the disease. Furthermore, a genotype–phenotype correlation in PAM may exist. http://bit.ly/3307M1p
Footnotes
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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.
Support statement: This work was supported by unrestricted grants from the Graduate School of Health Aarhus University, MEMBRANES Aarhus University, Central Denmark Region, Fonden til Lægevidenskabens Fremme A.P. Møller og Hustru Chastine Mc-Kinney Møllers Fond til almene Formaal, the Novo Nordisk Foundation (grant number NNF60C0023284), and the LAM Foundation. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received April 22, 2019.
- Accepted November 15, 2019.
- Copyright ©ERS 2020
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