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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., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

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., Competing Interests: 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., (Copyright ©ERS 2020.)

Idiopathic interstitial pneumonias (IIPs) comprise a heterogeneous group of rare lung parenchyma disorders with high morbidity and mortality, which can occur at all ages. In adults, the most common form of IIPs, idiopathic pulmonary fibrosis (IPF), has been associated with an increased frequency of lung cancer. The molecular basis of IIPs remains unknown in most cases. This study investigates IIP pathophysiology in 12 families affected by IPF and lung cancer. We identified, in a multigenerational family, nine members carrying a heterozygous missense mutation with evidence of pathogenicity in SFTPA1 that encodes the surfactant protein (SP)-A1. The mutation (p.Trp211Arg), which segregates with a disease phenotype characterized by either isolated IIP/IPF, or IPF associated with lung adenocarcinoma, is located in the carbohydrate recognition domain (CRD) of SP-A1 and involves a residue invariant throughout evolution, not only in SP-A1, but also in its close paralog SP-A2 and other CRD-containing proteins. As shown through functional studies, the p.Trp211Arg mutation impairs SP-A1 secretion. Immunohistochemistry studies on patient alveolar epithelium showed an altered SP-A expression pattern. Overall, this first report of a germline molecular defect in SFTPA1 unveils the key role of SP-A1 in the occurrence of several chronic respiratory diseases, ranging from severe respiratory insufficiency occurring early in life to the association of lung fibrosis and cancer in adult patients. These data also clearly show that, in spite of their structural and functional similarities, SP-A1 and SP-A2 are not redundant., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background and Objectives: Gitelman syndrome (GS) is a salt-wasting tubulopathy that results from the inactivation of the human thiazide-sensitive sodium chloride cotransporter located in the distal convoluted tubule. Tubular adaptation to renal sodium loss has been described and localized in the distal tubule in experimental models of GS but not in humans with GS., Design, Setting, Participants, & Measurements: The tubular adaptation to renal sodium loss is described. Osmole-free water clearance and endogenous lithium clearance with furosemide infusion are used to compare 7 patients with genetically confirmed GS and 13 control participants., Results: Neither endogenous lithium clearance nor osmole-free water clearance disclosed enhanced proximal fluid reabsorption in patients with GS. These patients displayed significantly lower osmole-free water clearance factored by inulin clearance (7.1 ± 1.9 versus 10.1 ± 2.2; P<0.01) and significantly lower fractional sodium reabsorption in the diluting nephron (73.2% ± 7.1% versus 86.1% ± 4.7%; P<0.005), consistent with the inactivation of the thiazide-sensitive sodium chloride cotransporter. The furosemide-induced reduction rate of fractional sodium reabsorption in the diluting segment was higher in patients with GS (75.6% ± 6.1% versus 69.9% ± 3.2%; P<0.039), suggesting that sodium reabsorption would be enhanced in the cortical part of the thick ascending limb of the loop of Henle in patients with GS., Conclusions: These findings suggest that tubular adaptation to renal sodium loss in GS would be devoted to the cortical part of the thick ascending limb of the loop of Henle in humans.

Germ-line mutations in the genes encoding succinate dehydrogenase complex subunits B (SDHB) and D (SDHD) have been reported in familial paragangliomas and apparently sporadic phaeochromocytomas (ASP), but the genotype-phenotype relationships of these mutations are unknown. Eighty-four patients (all but 2 followed up for 8.8 +/- 5.7 years) with ASP (57 with adrenal tumors, 27 with extra-adrenal, multiple, malignant, or recurrent tumors) were screened for the major susceptibility genes for phaeochromocytoma (RET, VHL, SDHD, and SDHB). Thirty-three tumors were available for molecular analysis, enzyme assays, and immunohistochemistry. No (0%) RET and 2 (2.4%) VHL mutations were detected. Only two coding single nucleotide polymorphisms in the SDHD gene (G12S and H50R) were found in 6 patients (7%). Conversely, six deleterious mutations in the SDHB gene were identified in 8 patients (9.5%). Ectopic site and recurrence or malignancy were strongly associated with SDHB mutations (7 of 8, 87%, versus 20 of 76, 26%; P = 0.001). Somatic DNA analysis indicated a loss of heterozygosity at chromosome 1p36 (SDHB locus) in 16 of 33 cases (48%). A loss of heterozygosity at the SDHB locus was found in all tumors with SDHB mutation, and assays of respiratory chain enzymes showed a complete loss of complex II catalytic activity. The vascular architecture of tumors with SDHB mutations displayed features typical of malignancy. These data strongly suggest that SDHB gene is a tumor suppressor gene and that the identification of germ-line mutations in SDHB gene in patients with ASPs should be considered as a high-risk factor for malignancy or recurrence.