Jensson Brynjar O, Hansdottir Sif, Arnadottir Gudny A, Sulem Gerald, Kristjansson Ragnar P, Oddsson Asmundur, Benonisdottir Stefania, Jonsson Hakon, Helgason Agnar, Saemundsdottir Jona, Magnusson Olafur T, Masson Gisli, Thorisson Gudmundur A, Jonasdottir Adalbjorg, Jonasdottir Aslaug, Sigurdsson Asgeir, Jonsdottir Ingileif, Petursdottir Vigdis, Kristinsson Jon R, Gudbjartsson Daniel F, Thorsteinsdottir Unnur, Arngrimsson Reynir, Sulem Patrick, Gudmundsson Gunnar, Stefansson Kari
deCODE Genetics/Amgen, Inc, Sturlugata 8, 101, Reykjavik, Iceland.
Department of Respiratory Medicine and Sleep, Landspitali University Hospital, Reykjavik, Iceland.
BMC Med Genet. 2017 Nov 14;18(1):129. doi: 10.1186/s12881-017-0490-8.
Rare missense mutations in the gene encoding coatomer subunit alpha (COPA) have recently been shown to cause autoimmune interstitial lung, joint and kidney disease, also known as COPA syndrome, under a dominant mode of inheritance.
Here we describe an Icelandic family with three affected individuals over two generations with a rare clinical presentation of lung and joint disease and a histological diagnosis of follicular bronchiolitis. We performed whole-genome sequencing (WGS) of the three affected as well as three unaffected members of the family, and searched for rare genotypes associated with disease using 30,067 sequenced Icelanders as a reference population. We assessed all coding and splicing variants, prioritizing variants in genes known to cause interstitial lung disease. We detected a heterozygous missense mutation, p.Glu241Lys, in the COPA gene, private to the affected family members. The mutation occurred de novo in the paternal germline of the index case and was absent from 30,067 Icelandic genomes and 141,353 individuals from the genome Aggregation Database (gnomAD). The mutation occurs within the conserved and functionally important WD40 domain of the COPA protein.
This is the second report of the p.Glu241Lys mutation in COPA, indicating the recurrent nature of the mutation. The mutation was reported to co-segregate with COPA syndrome in a large family from the USA with five affected members, and classified as pathogenic. The two separate occurrences of the p.Glu241Lys mutation in cases and its absence from a large number of sequenced genomes confirms its role in the pathogenesis of the COPA syndrome.
编码外被体亚基α（COPA）的基因中罕见的错义突变最近被证明在显性遗传模式下可导致自身免疫性间质性肺病、关节病和肾病，也称为COPA综合征。
在此，我们描述了一个冰岛家族，两代中有三名患者，临床表现为罕见的肺部和关节疾病，组织学诊断为滤泡性细支气管炎。我们对该家族的三名患者以及三名未受影响的成员进行了全基因组测序（WGS），并以30,067名已测序的冰岛人作为参考人群，寻找与疾病相关的罕见基因型。我们评估了所有编码和剪接变异，优先考虑已知可导致间质性肺病的基因中的变异。我们在COPA基因中检测到一个杂合错义突变p.Glu241Lys，该突变是受影响家庭成员所特有的。该突变在索引病例的父系生殖细胞中从头发生，在30,067个冰岛基因组和基因组聚合数据库（gnomAD）的141,353个人中均未出现。该突变发生在COPA蛋白保守且功能重要的WD40结构域内。
这是COPA基因中p.Glu241Lys突变的第二篇报道，表明该突变具有复发性。据报道，该突变在美国一个有五名受影响成员的大家族中与COPA综合征共分离，并被分类为致病性突变。该p.Glu241Lys突变在两个独立病例中的出现以及在大量已测序基因组中的缺失证实了其在COPA综合征发病机制中的作用。
