Abstract
Introduction Interstitial lung diseases (ILDs) can be caused by mutations in the SFTPA1 and SFTPA2 genes, which encode the surfactant protein (SP) complex SP-A. Only 11 SFTPA1 or SFTPA2 mutations have so far been reported worldwide, of which five have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic SFTPA1 or SFTPA2 mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives.
Methods The consequences of the 11 SFTPA1 or SFTPA2 mutations were analysed both in vitro, by studying the production and secretion of the corresponding mutated proteins and ex vivo, by analysing SP-A expression in lung tissue samples. The associated disease phenotypes were documented.
Results For the 11 identified mutations, protein production was preserved but secretion was abolished. The expression pattern of lung SP-A available in six patients was altered and the family history reported ILD and/or lung adenocarcinoma in 13 out of 14 families (93%). Among the 28 SFTPA1 or SFTPA2 mutation carriers, the mean age at ILD onset was 45 years (range 0.6–65 years) and 48% underwent lung transplantation (mean age 51 years). Seven carriers were asymptomatic.
Discussion This study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic SFTPA1 or SFTPA2 mutations share similar consequences for SP-A secretion in cell models and in lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of disease, ranging from severe forms requiring lung transplantation to incomplete penetrance.
Abstract
SFTPA1 and SFTPA2 mutations lead to similar alterations in SP-A secretion and lung tissue expression. They are associated with a highly variable phenotypic expression ranging from incomplete penetrance to severe interstitial lung diseases and lung cancer. https://bit.ly/30SrEVb
Footnotes
This article has an editorial commentary: https://doi.org/10.1183/13993003.03252-2020
This article has supplementary material available from erj.ersjournals.com
Author contributions: N. Nathan, M. Legendre, A. Clement and S. Amselem designed the study; N. Nathan, A. Butt, E. Filhol-Blin, T. Desroziers, M. Héry, V. Nau and A. Coulomb L'Hermine performed the experiments; N. Nathan, M. Legendre, B. Copin, P. Duquesnoy, E. Filhol-Blin, T. Desroziers, M. Héry, A. Butt, A. Coulomb L'Hermine, M-P. Debray, A. Clement and S. Amselem analysed and interpreted the data; N. Nathan and A. Butt wrote the manuscript; M. Legendre, S. Amselem, A. Clement, B. Copin, M-P. Debray, A. Coulomb L'Hermine, R. Borie, F. Dastot Le Moal, C. Kannengiesser, L. Gouya, V. Cottin, J. Traclet, B. Crestani, A. Gondouin, C. Dupin, C. Dombret, A. Cazes, A-L. Chene, V. Giraud, H. Nunes, D. Bouvry, A. Bergeron, G. Lorillon, D. Israël-Biet, P. de Vuyst, C. Picard, E. Longchampt, M. Reynaud-Gaubert, J-C. Dalphin, S. Leroy, A. Le Borgne and N. Allou provided the patient data; all authors reviewed and approved the manuscript.
Conflict of interest: M. Legendre has nothing to disclose.
Conflict of interest: A. Butt has nothing to disclose.
Conflict of interest: R. Borie reports grants and personal fees from Boehringer Ingelheim and Roche, and personal fees from Savapharma, outside the submitted work.
Conflict of interest: M-P. Debray has nothing to disclose.
Conflict of interest: D. Bouvry has nothing to disclose.
Conflict of interest: E. Filhol-Blin has nothing to disclose.
Conflict of interest: T. Desroziers has nothing to disclose.
Conflict of interest: V. Nau has nothing to disclose.
Conflict of interest: B. Copin has nothing to disclose.
Conflict of interest: F. Dastot Le Moal has nothing to disclose.
Conflict of interest: M. Héry has nothing to disclose.
Conflict of interest: P. Duquesnoy has nothing to disclose.
Conflict of interest: N. Allou has nothing to disclose.
Conflict of interest: A. Bergeron has nothing to disclose.
Conflict of interest: J. Bermudez has nothing to disclose.
Conflict of interest: A. Cazes has been invited to national and international meetings, and/or has received grants and/or personal fees for various activities from Boehringer Ingelheim and Roche, outside the submitted work.
Conflict of interest: A-L. Chene has nothing to disclose.
Conflict of interest: V. Cottin reports personal fees for lectures and advisory board work and non-financial support for meeting attendance from Actelion; grants, personal fees for lectures and advisory board work, and non-financial support for meeting attendance from Boehringer Ingelheim; personal fees for advisory board and data monitoring committee work from Bayer/MSD and Galapagos; personal fees for lectures and advisory board work from Novartis; personal fees for lectures, consultancy, data monitoring committee and steering committee work, and non-financial support for meeting attendance from Roche/Promedior; personal fees for lectures from Sanofi and AstraZeneca; personal fees for data monitoring committee work from Celgene and Galecto; and personal fees for advisory board work from Shionogi, outside the submitted work.
Conflict of interest: B. Crestani has nothing to disclose.
Conflict of interest: J-C. Dalphin has nothing to disclose.
Conflict of interest: C. Dombret has nothing to disclose.
Conflict of interest: B. Doray has nothing to disclose.
Conflict of interest: C. Dupin reports personal fees for lectures and advisory board work, and non-financial support and meeting invitations from AstraZeneca; personal fees for lectures, non-financial support and meeting invitations from Boehringer and Novartis; personal fees for research and lectures, and non-financial support and meeting invitations from GSK; personal fees for lectures and meeting invitations from Chiesi; personal fees for lectures and advisory board work, and non-financial support from Sanofi; and personal fees, non-financial support and meeting invitations from Roche, outside the submitted work.
Conflict of interest: V. Giraud has nothing to disclose.
Conflict of interest: A. Gondouin has nothing to disclose.
Conflict of interest: L. Gouya has nothing to disclose.
Conflict of interest: D. Israël-Biet has nothing to disclose.
Conflict of interest: C. Kannengiesser has nothing to disclose.
Conflict of interest: A. Le Borgne has nothing to disclose.
Conflict of interest: S. Leroy has nothing to disclose.
Conflict of interest: E. Longchampt has nothing to disclose.
Conflict of interest: G. Lorillon has nothing to disclose.
Conflict of interest: H. Nunes has nothing to disclose.
Conflict of interest: C. Picard has nothing to disclose.
Conflict of interest: M. Reynaud-Gaubert has nothing to disclose.
Conflict of interest: J. Traclet has nothing to disclose.
Conflict of interest: P. de Vuyst has nothing to disclose.
Conflict of interest: A. Coulomb L'Hermine has nothing to disclose.
Conflict of interest: A. Clement has nothing to disclose.
Conflict of interest: S. Amselem has nothing to disclose.
Conflict of interest: N. Nathan reports a 2018 AstraZeneca Mobility Grant from Société de pneumologie pédiatrique et d'allergologie (France), outside the submitted work.
Support statement: This work was supported by grants from the Institut National de la Santé et la Recherche Médicale (INSERM), the Legs Poix from the Chancellerie des Universités de Paris (grants 2013 number 1305, 2014 number 1405, 2015 number 1015, 2016 number 2077 and 2017 number DP2017/1860), the Société Française de Pédiatrie - Société Pédiatrique de Pneumologie et d'Allergologie and AstraZeneca, as well as funding from the patient organisationsRespirer c'est Grandir and the Belleherbe Association. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received April 26, 2020.
- Accepted July 22, 2020.
- Copyright ©ERS 2020