A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.,Human Genome Variation

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A novel germline mutation of the SFTPA1 gene in familial interstitial pneumonia.
Human Genome Variation ( IF 1.0 ) Pub Date : 2019-03-05 , DOI: 10.1038/s41439-019-0044-z
Martina Doubková ₁ , Kateřina Staňo Kozubík _{2,

3} , Lenka Radová ₂ , Michaela Pešová ₂ , Jakub Trizuljak _{2,

3} , Karol Pál ₂ , Klára Svobodová ₂ , Kamila Réblová ₂ , Hana Svozilová _{2,

3} , Zuzana Vrzalová _{2,

3} , Šárka Pospíšilová _{2,

3} , Michael Doubek _{2,

3}

Affiliation

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.

中文翻译：

家族性间质性肺炎中 SFTPA1 基因的一种新的种系突变。

与肺泡稳定性相关的不同基因与家族性间质性肺炎（FIP）有关。在这里，我们在特发性间质性肺炎 (IIP) 家族中报告了一种新的、罕见的 SFTPA1 变异。我们对来自一个家族的四个成员的种系 DNA 样本进行了全外显子组测序；其中三人表现出具有常染色体显性遗传的肺纤维化（特发性间质性肺炎）的迹象。已鉴定出 SFTPA1 基因中的杂合单核苷酸变体 c.532 G > A。该变体编码取代 p.(Val178Met)，位于表面活性蛋白 A 的碳水化合物识别域内，并与导致特发性间质性肺炎的基因分离。这种罕见的变种以前没有报道过。我们还分析了在计算机中检测到的蛋白质结构中的序列变体。缬氨酸被蛋白质中较大的蛋氨酸取代可能会导致蛋白质结构的破坏。使用扩增子的 Sanger 测序进一步验证了 c.532 G > A 变体，确认了所有有症状的家庭成员的诊断。此外，通过 Sanger 测序在另一名有症状的家庭成员和一名年轻的无症状家庭成员中也发现了这种变异。常染色体显性遗传、IIP 的家族史以及部分 SFTPA1 基因发生突变的证据都表明存在导致 FIP 的新变异。使用扩增子的 Sanger 测序进一步验证了一个变体，确认了所有有症状的家庭成员的诊断。此外，通过 Sanger 测序在另一名有症状的家庭成员和一名年轻的无症状家庭成员中也发现了这种变异。常染色体显性遗传、IIP 的家族史以及部分 SFTPA1 基因发生突变的证据都表明存在导致 FIP 的新变异。使用扩增子的 Sanger 测序进一步验证了一个变体，确认了所有有症状的家庭成员的诊断。此外，通过 Sanger 测序在另一名有症状的家庭成员和一名年轻的无症状家庭成员中也发现了这种变异。常染色体显性遗传、IIP 的家族史以及部分 SFTPA1 基因发生突变的证据都表明存在导致 FIP 的新变异。

更新日期：2019-11-18

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