Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer
Marie Legendre
(1, 2)
,
Afifaa Butt
(1, 2)
,
Raphaël Borie
(3)
,
Marie-Pierre Debray
(3)
,
Diane Bouvry
(4, 5)
,
Emilie Filhol-Blin
(2)
,
Tifenn Desroziers
(1)
,
Valérie Nau
(2)
,
Bruno Copin
(2, 1)
,
Florence Dastot-Le Moal
(2)
,
Mélanie Héry
(1)
,
Philippe Duquesnoy
(1)
,
Nathalie Allou
(6)
,
Anne Bergeron
(7)
,
Julien Bermudez
(8, 9, 10)
,
Aurélie Cazes
(3)
,
Anne-Laure Chene
(11)
,
Vincent Cottin
(12, 13)
,
Bruno Crestani
(3)
,
Jean-Charles Dalphin
(14, 15)
,
Christine Dombret
(3)
,
Bérénice Doray
(6)
,
Clairelyne Dupin
(7)
,
Violaine Giraud
(16)
,
Anne Gondouin
(14, 15)
,
Laurent Gouya
(7)
,
Dominique Israël-Biet
(17)
,
Caroline Kannengiesser
(3)
,
Aurélie Le Borgne
(18)
,
Sylvie Leroy
(19)
,
Elisabeth Longchampt
(20)
,
Gwenaël Lorillon
(7)
,
Hilario Nunes
(4, 5)
,
Clément Picard
(20)
,
Martine Reynaud-Gaubert
(8, 9, 10)
,
Julie Traclet
(12, 13)
,
Paul de Vuyst
(21)
,
Aurore Coulomb L'Hermine
(22)
,
Annick Clement
(1, 23)
,
Serge Amselem
(1, 2)
,
Nadia Nathan
(1, 23)
1
Inserm U933 -
Maladies génétiques d'expression pédiatrique [CHU Trousseau]
2 UF de Génétique moléculaire [CHU Trousseau]
3 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
4 H&P - Hypoxie et Poumon : pneumopathologies fibrosantes, modulations ventilatoires et circulatoires
5 Hôpital Avicenne [AP-HP]
6 Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion]
7 AP-HP - Hopital Saint-Louis [AP-HP]
8 Hôpital Nord [CHU - APHM]
9 MEPHI - Microbes évolution phylogénie et infections
10 IHU Marseille - Institut Hospitalier Universitaire Méditerranée Infection
11 CHU Nantes - Centre hospitalier universitaire de Nantes
12 HCL - Hospices Civils de Lyon
13 UCBL - Université Claude Bernard Lyon 1
14 LCE - Laboratoire Chrono-environnement (UMR 6249)
15 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
16 Hôpital Ambroise Paré [AP-HP]
17 HEGP - Hôpital Européen Georges Pompidou [APHP]
18 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
19 CHU - Hôpital Pasteur [Nice]
20 Hôpital Foch [Suresnes]
21 Hôpital Erasme [Bruxelles]
22 CHU Trousseau [APHP]
23 Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau]
2 UF de Génétique moléculaire [CHU Trousseau]
3 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
4 H&P - Hypoxie et Poumon : pneumopathologies fibrosantes, modulations ventilatoires et circulatoires
5 Hôpital Avicenne [AP-HP]
6 Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion]
7 AP-HP - Hopital Saint-Louis [AP-HP]
8 Hôpital Nord [CHU - APHM]
9 MEPHI - Microbes évolution phylogénie et infections
10 IHU Marseille - Institut Hospitalier Universitaire Méditerranée Infection
11 CHU Nantes - Centre hospitalier universitaire de Nantes
12 HCL - Hospices Civils de Lyon
13 UCBL - Université Claude Bernard Lyon 1
14 LCE - Laboratoire Chrono-environnement (UMR 6249)
15 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
16 Hôpital Ambroise Paré [AP-HP]
17 HEGP - Hôpital Européen Georges Pompidou [APHP]
18 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
19 CHU - Hôpital Pasteur [Nice]
20 Hôpital Foch [Suresnes]
21 Hôpital Erasme [Bruxelles]
22 CHU Trousseau [APHP]
23 Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau]
Marie Legendre
- Function : Author
- PersonId : 1147534
- IdHAL : marie-legendre
- ORCID : 0000-0003-2178-0846
Raphaël Borie
- Function : Author
- PersonId : 770718
- ORCID : 0000-0002-9906-0024
- IdRef : 081295626
Tifenn Desroziers
- Function : Author
- PersonId : 1183888
- IdHAL : tifenn-desroziers
- ORCID : 0000-0001-7071-5173
Bruno Copin
- Function : Author
- PersonId : 1176543
- IdHAL : bruno-copin
Florence Dastot-Le Moal
- Function : Author
- PersonId : 1182834
- IdHAL : florence-dastot-le-moal
- ORCID : 0000-0001-7368-5344
Julien Bermudez
- Function : Author
- PersonId : 799476
- ORCID : 0000-0001-8823-0959
Vincent Cottin
- Function : Author
- PersonId : 784269
- ORCID : 0000-0002-5591-0955
- IdRef : 166774731
Clairelyne Dupin
- Function : Author
- PersonId : 1169550
- ORCID : 0000-0001-7957-8195
Caroline Kannengiesser
- Function : Author
- PersonId : 1169551
- ORCID : 0000-0003-2155-9383
Aurore Coulomb L'Hermine
- Function : Author
- PersonId : 1169552
- ORCID : 0000-0002-0945-7379
Serge Amselem
- Function : Author
- PersonId : 936326
- IdHAL : serge-amselem
- ORCID : 0000-0001-9506-3968
Nadia Nathan
Connectez-vous pour contacter l'auteur
- Function : Correspondent author
- PersonId : 1029287
- IdHAL : nadianathan
- ORCID : 0000-0001-5149-7975
Connectez-vous pour contacter l'auteur
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.
Domains
Human genetics
Embargoed file
Embargoed file
Ne sera jamais visible