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Copy number variations and founder effect underlying complete IL-10Rβ deficiency in Portuguese kindreds.

Fabienne Charbit-Henrion 1, 2, 3 Bernadette Bègue 1, 3 Anaïs Sierra 1, 3 Sylvain Hanein 4 Marie-Claude Stolzenberg 5 Zhi Li 6 Sandra Pellegrini 6 Nicolas Garcelon 7 Marc Jeanpierre 8, 9 Bénédicte Neven 10, 5 Isabelle Loge 11 Capucine Picard 8, 12 Jeremie Rosain 12, 13 Jacinta Bustamante 4, 14, 12 Marc Le Lorc'H 15 Benedicte Pigneur 2, 1, 3 Alicia Fernandes 16, 4 Frédéric Rieux-Laucat 5 Jorge Amil Dias 17, 3 Frank Ruemmele 2, 1, 3 Nadine Cerf-Bensussan 1
1 Equipe Inserm U1163 - Laboratory of Intestinal Immunity
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
2 Service de Gastroentérologie, d'hépatologie et nutrition pédiatrique [CHU Necker]
3 GENIUS Group
4 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
5 Equipe Inserm U1163 - Immunogenetics of pediatric autoimmune diseases
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
6 Signalisation des Cytokines
7 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
8 UPD5 - Université Paris Descartes - Paris 5
9 Service de Génétique [Cochin]
10 Service d'immuno-hématologie pédiatrique [CHU Necker]
11 Hôpital Charles Nicolle [Rouen]
12 CHU Necker - Enfants Malades [AP-HP]
13 Equipe Inserm U1163 - Human genetics of infectious diseases : Mendelian predisposition
IMAGINE - U1163 - Imagine - Institut des maladies génétiques
14 St. Giles Laboratory of Human Genetics of Infectious Diseases
15 Laboratoire Histologie Embryologie Cytogénétique [CHU Necker]
16 SFR Necker - UMS 3633 / US24 - Structure Fédérative de Recherche Necker
17 Centro Hospitalar São João EPE
Abstract : Mutations in interleukin-10 receptor (IL-10R) genes are one cause of very early-onset inflammatory bowel disease with perianal lesions, which can be cured by hematopoietic stem cell transplantation. Using a functional test, which assesses responsiveness of peripheral monocytes to IL-10, we identified three unrelated Portuguese patients carrying two novel IL-10RB mutations. In the three patients, sequencing of genomic DNA identified the same large deletion of exon 3 which precluded protein expression. This mutation was homozygous in two patients born from consanguineous families and heterozygous in the third patient born from unrelated parents. Microsatellite analysis of the IL10RB genomic region revealed a common haplotype in the three Portuguese families pointing to a founder deletion inherited from a common ancestor 400 years ago. In the third patient, surface expression of IL-10R was normal but signaling in response to IL-10 was impaired. Complementary DNA sequencing and next-generation sequencing of IL10RB locus with custom-made probes revealed a ≈ 6 Kb duplication encompassing the exon 6 which leads to a frameshift mutation and a loss of the TYK2-interacting Box 2 motif. Altogether, we describe two novel copy number variations in IL10RB, one with founder effect and one preserving cell surface expression but abolishing signaling.
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Fabienne Charbit-Henrion, Bernadette Bègue, Anaïs Sierra, Sylvain Hanein, Marie-Claude Stolzenberg, et al.. Copy number variations and founder effect underlying complete IL-10Rβ deficiency in Portuguese kindreds.. PLoS ONE, Public Library of Science, 2018, 13 (10), pp.e0205826. ⟨10.1371/journal.pone.0205826⟩. ⟨pasteur-02070998⟩

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