A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia

Abstract

Different genes related to alveolar stability have been associated with familial interstitial pneumonia (FIP). Here, we report a novel, rare SFTPA1 variant in a family with idiopathic interstitial pneumonia (IIP). We performed whole-exome sequencing on germline DNA samples from four members of one family; three of them showed signs of pulmonary fibrosis (idiopathic interstitial pneumonia) with autosomal-dominant inheritance. A heterozygous single nucleotide variant c.532 G > A in the SFTPA1 gene has been identified. This variant encodes the substitution p.(Val178Met), localized within the carbohydrate recognition domain of surfactant protein A and segregates with the genes causing idiopathic interstitial pneumonia. This rare variant has not been previously reported. We also analyzed the detected sequence variant in the protein structure in silico . The replacement of valine by the larger methionine inside the protein may cause a disruption in the protein structure. The c.532 G > A variant was further validated using Sanger sequencing of the amplicons, confirming the diagnosis in all symptomatic family members. Moreover, this variant was also found by Sanger sequencing in one other symptomatic family member and one young asymptomatic family member. The autosomal-dominant inheritance, the family history of IIP, and the evidence of a mutation occurring in part of the SFTPA1 gene all suggest a novel variant that causes FIP.

Genetic Risk Factors for Idiopathic Pulmonary Fibrosis: Insights into Immunopathogenesis

“…Rare variants in the two adjacent SP-A coding genes, SFTPA1 and SFTPA2, have been described in several cases of FIP. [113][114][115] While the role that these and other surfactant-related variants play in contribution to sporadic IPF remains less clear, IPF patients have been reported to have reduced BAL concentrations of SP-A compared to healthy patients, and SP-A levels are inversely correlated with survival. 116,117 Mice deficient in SP-A (SP-A −/-) show dramatically decreased bacterial clearance, impaired macrophage phagocytosis, and increased production of pro-inflammatory cytokines IL-1β, IL-6, and TNF which are also associated with fibroblast activation.…”

Pulmonary Fibrosis in Children

“…Interestingly, in large next generation sequencing (NGS) or whole exome sequencing (WES) studies including IPF patients with a histologic UIP attested by the ATS/ERS criteria (2011), a few SFTPC and biallelic ABCA3 mutations were identified [11,28]. SP-A-related disorders were more recently associated with ILD [17,18,28,29]. They were alternatively associated on HRCT scans and histology of the lung with UIP, NSIP, and even DIP patterns [30].…”

Genetic disorders of the surfactant system: focus on adult disease

“…Thereafter three other families were described, each with their own unique exon 6 SFTPA1 mutation [97][98][99], including the homozygous adult sons of consanguineous heterozygous Japanese parents [99]. The parents were asymptomatic but, upon examination, subclinical disease with a D LCO <63% predicted was detected [100].…”

“…HRCT of SFTPA1 and SFTPA2 mutation carriers is difficult to classify, but most commonly contains septal thickening and GGOs and may be described as NSIP [95,97,99]. The few histological descriptions of SFTPA mutation carriers most often describe a pattern of UIP, but NSIP, DIP and organising pneumonia (OP) have also been mentioned [93,95,97,99].…”