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Hypomorphic pathogenic variant in SFTPB leads to adult pulmonary fibrosis

European Journal of Human Genetics volume 31, pages 1083–1087 (2023)Cite this article

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Abstract

Biallelic pathogenic variants in the surfactant protein (SP)-B gene (SFTPB) have been associated with fatal forms of interstitial lung diseases (ILD) in newborns and exceptional survival in young children. We herein report the cases of two related adults with pulmonary fibrosis due to a new homozygous SFTPB pathogenic variant, c.582G>A p.(Gln194=). In vitro transcript studies showed that this SFTPB synonymous pathogenic variant induces aberrant splicing leading to three abnormal transcripts with the preservation of the expression of a small proportion of normal SFTPB transcripts. Immunostainings on lung biopsies of the proband showed an almost complete loss of SP-B expression. This hypomorphic splice variant has thus probably allowed the patients’ survival to adulthood while inducing an epithelial cell dysfunction leading to ILD. Altogether, this report shows that SFTPB pathogenic variants should be considered in atypical presentations and/or early-onset forms of ILD particularly when a family history is identified.

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Fig. 1: Family tree, CT scan and histological features.
Fig. 2: In vitro assessment of SFTPB splicing defects associated with c.582G>A p.(Gln194=).

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the patients and their family. We thank the French national networks for rare lung diseases: Centre de référence des maladies respiratoires rares (RespiRare), Centre de référence des maladies pulmonaires rares (OrphaLung) and Filière de soins pour les maladies respiratoires rares (RespiFIL). The ILD cohort has been developed in collaboration with the Rare Disease Cohort (RaDiCo)-ILD project (ANR-10-COHO-0003), the ERS Clinical research collaboration for chILD-EU and the COST Innovative Grant OpenILD CIG16125.

Funding

Our work is supported by the Legs Poix from the Chancellerie des Universités (grants 2013 n°1305, 2014 n°1405, 2015 n°1015, 2016 n°2077, 2017 n°DP2017/1860 and 2022 n°2022000594).

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Author notes

  1. These authors contributed equally: Marie Legendre, Nadia Nathan.

Authors and Affiliations

  1. Inserm UMR_S933, Laboratory of Childhood Genetic Diseases, Armand Trousseau Hospital, Sorbonne Université, Paris, France

    Tifenn Desroziers, Philippe Duquesnoy, Mélanie Héry, Serge Amselem, Marie Legendre & Nadia Nathan

  2. Respiratory Medicine, Toulouse University Hospital, Toulouse, France

    Grégoire Prévot & Aurélie Le Borgne

  3. Assistance Publique – Hôpitaux de Paris, Pathology Department, Armand Trousseau Hospital, Sorbonne Université, Paris, France

    Aurore Coulomb

  4. Assistance Publique – Hôpitaux de Paris, Molecular Genetics Unit, Armand Trousseau Hospital, Sorbonne Université, Paris, France

    Valérie Nau, Florence Dastot-Le Moal, Serge Amselem & Marie Legendre

  5. Assistance Publique – Hôpitaux de Paris, Pediatric Pulmonology Department and Reference Center for Rare Lung Diseases RespiRare, Armand Trousseau Hospital, Sorbonne Université, Paris, France

    Nadia Nathan

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  1. Tifenn Desroziers
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Contributions

TD and NN performed the functional studies and wrote the manuscript that was reviewed by all the authors. ML contributed to the data analysis. PD provided his expertise in functional studies. GP and ALB were in charge of the patients. VN and FDL performed the molecular diagnosis under the supervision of ML and SA. AC performed the histological analyses.

Corresponding author

Correspondence to Nadia Nathan.

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The authors declare no competing interests.

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Written informed consents were obtained from the two patients. Ethical approval was obtained from the local authorities under the number 060916.

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Desroziers, T., Prévot, G., Coulomb, A. et al. Hypomorphic pathogenic variant in SFTPB leads to adult pulmonary fibrosis. Eur J Hum Genet 31, 1083–1087 (2023). https://doi.org/10.1038/s41431-023-01413-w

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