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PLoS One. 2018 Oct 26;13(10):e0205826. doi: 10.1371/journal.pone.0205826. eCollection 2018.

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

Author information

1
INSERM, UMR1163 and Institut Imagine, Laboratory of Intestinal Immunity, Paris, France.
2
Paris Descartes University-Sorbonne Paris Cité, Paris, France.
3
Department of Paediatric Gastroenterology, Hepatology and Nutrition, Necker-Enfants Malades Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France.
4
GENIUS group, Paris, France.
5
INSERM UMR1163 and Institut Imagine, Translational Genetic, Paris, France.
6
INSERM UMR1163 and Institut Imagine, Immunogenetics of Paediatric Autoimmunity, Paris, France.
7
Cytokine Signaling Unit, Institut Pasteur, INSERM 1221, Paris, France.
8
INSERM, Centre de Recherche des Cordeliers, UMR 1138 Equipe 22, Institut Imagine, Paris France.
9
Genetic Unit, Cochin Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France.
10
Paediatric Haematology-Immunology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France.
11
Department of Paediatrics, Hôpital Charles-Nicolle, CHU Rouen, Rouen, France.
12
Study Centre for Primary Immunodeficiency, Necker-Enfants Malades Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France.
13
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163 and Institut Imagine, Necker Hospital for Sick Children, Paris, France.
14
St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, New York, United States of America.
15
Histology, Embryology and Cytogenetics Unit, Necker-Enfants Malades Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France.
16
Centre of Biological Resources, Structure Fédérative de Recherche Necker, INSERM US24, CNRS UMS3633, Assistance Publique des Hôpitaux de Paris (AP-HP), and Institut Imagine, Paris, France.
17
Department of Paediatrics, Centro Hospitalar S. João, Porto, Portugal.

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.

PMID:
30365510
DOI:
10.1371/journal.pone.0205826
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Conflict of interest statement

The authors have declared that no competing interests exist.

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