Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer

Abstract

IntroductionInterstitial lung diseases (ILD) can be caused by mutations in the SFTPA1 and SFTPA2 genes, which encode the surfactant protein complex (SP)-A. Only 11 SFTPA1/2 mutations have so far been reported worldwide, of which 5 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.MethodsThe consequences of the 11 SFTPA1/2 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 on lung tissue samples. The associated disease phenotypes were documented.ResultsFor the 11 identified mutations, protein production was preserved, but secretion was abolished. The expression pattern of lung SP-A, available in 6 patients, was altered. The family history reported ILD and/or lung adenocarcinoma in 13/14 (93%) families. Among the 28 SFTPA1/2 mutation carriers, the mean age at ILD onset was 45 [0.6–65] years and 48% of them underwent lung transplantation (mean age 51); 7 carriers were asymptomatic.DiscussionThis study, which expands the molecular and clinical spectrum of SP-A disorders, shows that those pathogenic SFTPA1/A2 mutations share similar consequences on SP-A secretion in cell models and lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of the disease, ranging from severe forms requiring lung transplantation to incomplete penetrance.

RaDiCo, the French national research program on rare disease cohorts

“…As for DNAJB13, it encodes an HSP40 family member involved in the proper building of the ciliary and flagellar axoneme [14]. In addition, besides Table 3 International publications so far associated to the RaDiCo program Discovery of new disease genes TTC12 loss-of function mutations cause primary ciliary dyskinesia and unveil distinct dynein assembly in motile cilia vs. flagella [11] Lack of GAS2L2 causes primary ciliary dyskinesia by impairing cilia orientation and mucociliary clearance [12] Mutations in outer dynein arm heavy chain DNAH9 cause motile cilia defects and situs inversus [13] Mutations in DNAJB13, encoding an HSP40 family member, cause primary ciliary dyskinesia and male infertility [14] de novo missense variants in FBXW11, a gene that encodes an F-box protein involved in ubiquitination and proteosomal degradation [15] Assessment of treatment management Vascular Ehlers-Danlos syndrome -Long-term observational study [16] Pathophysiology and diagnostic approaches Accuracy of clinical diagnostic criteria for patients with vascular Ehlers-Danlos syndrome in a tertiary referral centre [17] Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer [18] Pulmonary fibrosis in children [19] Chronic interstitial lung diseases in children: diagnosis approaches [20] Pulmonary hemosiderosis in children with Down syndrome: a national experience [21] Paediatric sarcoidosis [22] Genetic causes and clinical management of pediatric interstitial lung diseases [23] Genotype-phenotype relationships Infertility in an adult cohort with primary ciliary dyskinesia: phenotype-gene association [24] Primary ciliary dyskinesia gene contribution in Tunisia: Identification of a major Mediterranean allele [25] Alport syndrome: a unified classification of genetic disorders of collagen IV α345 [26] Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia [27] Development and validation of burden questionnaires and Quality of life Burden of albinism: development and validation of a burden assessment tool [28] Burden of adult neurofibromatosis 1: development and validation of a burden assessment tool [29] Health-related quality of life in infants and children with interstitial lung disease [30] Methodological aspects Federating patients identities: the case of rare diseases [10] Cerberus, an access control s...…”

“…Pathophysiology and diagnostic approaches-Several aspects were explored: Accuracy of clinical diagnostic criteria for patients with vascular Ehlers-Danlos syndrome in a tertiary reference center for the RaDiCo-SED-Vasc cohort [17]; In the RaDiCo-PID cohort, functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer [18]; Pulmonary fibrosis in children [19]; Diagnosis approaches of chronic interstitial lung diseases in children: [20][21][22]; or genetic causes and clinical management of pediatric interstitial lung diseases [23].…”

Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study

“…Idiopathic pulmonary fibrosis (IPF) Molecular explorations were performed by Sanger sequncing, capture-based next-generation sequencing panels (Haloplex/Agilent or Nimblegen/Roche), or whole-exome sequencing, as previously described [12, 19]. Germ line variants were interpreted according to the American College of Genetics and Genomics guidelines and the European Society for Human Genetics recommendations [23].…”

Lung Microbiome in Idiopathic Pulmonary Fibrosis and Other Interstitial Lung Diseases

“…Factors leading to disease initiation and progression are not fully understood for most of ILDs, although the interaction between genetic and environmental factors is believed to be a major driver of disease pathogenesis [2]. While a number of genetic variants that are potentially pathogenic are well recognized, the environmental triggers remain largely unidentified [3][4][5].…”