TY - JOUR
T1 - Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D
AU - Meeths, Marie
AU - Chiang, Samuel C C
AU - Wood, Stephanie M
AU - Entesarian, Miriam
AU - Schlums, Heinrich
AU - Bang, Benedicte
AU - Nordenskjöld, Edvard
AU - Björklund, Caroline
AU - Jakovljevic, Gordana
AU - Jazbec, Janez
AU - Hasle, Henrik
AU - Holmqvist, Britt-Marie
AU - Rajic, Ljubica
AU - Pfeifer, Susan
AU - Rosthøj, Steen
AU - Sabel, Magnus
AU - Salmi, Toivo T
AU - Stokland, Tore
AU - Winiarski, Jacek
AU - Ljunggren, Hans-Gustaf
AU - Fadeel, Bengt
AU - Nordenskjöld, Magnus
AU - Henter, Jan-Inge
AU - Bryceson, Yenan T
PY - 2011
Y1 - 2011
N2 - Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive, often-fatal hyperinflammatory disorder. Mutations in PRF1, UNC13D, STX11, and STXBP2 are causative of FHL2, 3, 4, and 5, respectively. In a majority of suspected FHL patients from Northern Europe, sequencing of exons and splice sites of such genes required for lymphocyte cytotoxicity revealed no or only monoallelic UNC13D mutations. Here, in 21 patients, we describe 2 pathogenic, noncoding aberrations of UNC13D. The first is a point mutation localized in an evolutionarily conserved region of intron 1. This mutation selectively impairs UNC13D transcription in lymphocytes, abolishing Munc13-4 expression. The second is a 253-kb inversion straddling UNC13D, affecting the 3'-end of the transcript and likewise abolishing Munc13-4 expression. Carriership of the intron 1 mutation was found in patients across Europe, whereas carriership of the inversion was limited to Northern Europe. Notably, the latter aberration represents the first description of an autosomal recessive human disease caused by an inversion. These findings implicate an intronic sequence in cell-type specific expression of Munc13-4 and signify variations outside exons and splice sites as a common cause of FHL3. Based on these data, we propose a strategy for targeted sequencing of evolutionary conserved noncoding regions for the diagnosis of primary immunodeficiencies.
AB - Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive, often-fatal hyperinflammatory disorder. Mutations in PRF1, UNC13D, STX11, and STXBP2 are causative of FHL2, 3, 4, and 5, respectively. In a majority of suspected FHL patients from Northern Europe, sequencing of exons and splice sites of such genes required for lymphocyte cytotoxicity revealed no or only monoallelic UNC13D mutations. Here, in 21 patients, we describe 2 pathogenic, noncoding aberrations of UNC13D. The first is a point mutation localized in an evolutionarily conserved region of intron 1. This mutation selectively impairs UNC13D transcription in lymphocytes, abolishing Munc13-4 expression. The second is a 253-kb inversion straddling UNC13D, affecting the 3'-end of the transcript and likewise abolishing Munc13-4 expression. Carriership of the intron 1 mutation was found in patients across Europe, whereas carriership of the inversion was limited to Northern Europe. Notably, the latter aberration represents the first description of an autosomal recessive human disease caused by an inversion. These findings implicate an intronic sequence in cell-type specific expression of Munc13-4 and signify variations outside exons and splice sites as a common cause of FHL3. Based on these data, we propose a strategy for targeted sequencing of evolutionary conserved noncoding regions for the diagnosis of primary immunodeficiencies.
U2 - 10.1182/blood-2011-07-369090
DO - 10.1182/blood-2011-07-369090
M3 - Journal article
SN - 0006-4971
VL - 118
SP - 5783
EP - 5793
JO - Blood
JF - Blood
ER -