2 research outputs found
COPA syndrome in an Icelandic family caused by a recurrent missense mutation in COPA
Background: 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.
Case presentation: 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.
Conclusions: 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.
Keywords: COPA syndrome, Lung disease, Arthritis, Immune dysregulation, Case reportPeer Reviewe
A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease
Publisher's version (útgefin grein)
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.Mutations in genes encoding subunits of the phagocyte NADPH oxidase complex are
recognized to cause chronic granulomatous disease (CGD), a severe primary immunodeficiency. Here we describe how deficiency of CYBC1, a previously uncharacterized protein in
humans (C17orf62), leads to reduced expression of NADPH oxidase’s main subunit (gp91phox)
and results in CGD. Analyzing two brothers diagnosed with CGD we identify a homozygous
loss-of-function mutation, p.Tyr2Ter, in CYBC1. Imputation of p.Tyr2Ter into 155K chipgenotyped Icelanders reveals six additional homozygotes, all with signs of CGD, manifesting
as colitis, rare infections, or a severely impaired PMA-induced neutrophil oxidative burst.
Homozygosity for p.Tyr2Ter consequently associates with inflammatory bowel disease (IBD)
in Iceland (P = 8.3 × 10−8; OR = 67.6), as well as reduced height (P = 3.3 × 10−4; −8.5 cm).
Overall, we find that CYBC1 deficiency results in CGD characterized by colitis and a distinct
profile of infections indicative of macrophage dysfunction.We wish to thank the family of the two probands, as well as all the other individuals who
participated in the study and whose contribution made this work possible.Peer Reviewe