Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds.

Abstract:

:Interleukin-12 (IL12) is a cytokine that is secreted by activated phagocytes and dendritic cells and that induces interferon-gamma production by natural-killer and T lymphocytes. It consists of two subunits, p35 and p40, which are encoded by IL12A and IL12B, respectively. The first reported patient with a genetic cytokine disorder was a Pakistani child, who was homozygous for a large loss-of-function deletion (g.482+82_856-854del) in IL12B. This IL12-deficient child suffered from infections caused by bacille Calmette-Guérin (BCG) and Salmonella enteritidis. We herein report 12 additional patients from five other kindreds. In one kindred from India, the same large deletion that was described elsewhere (g.482+82_856-854del) was identified. In four kindreds from Saudi Arabia, a recessive loss-of-function frameshift insertion (g.315_316insA) was found. A conserved haplotype encompassing the IL12B gene suggested that a founder effect accounted for the recurrence of each mutation. The two founder mutational events-g.482+82_856-854del and g.315_316insA-were estimated to have occurred approximately 700 and approximately 1,100 years ago, respectively. Among a total of 13 patients with IL12 deficiency, 1 child had salmonellosis only and 12 suffered from clinical disease due to BCG or environmental nontuberculous mycobacteria. One patient also had clinical disease caused by virulent Mycobacterium tuberculosis, five patients had clinical disease caused by Salmonella serotypes, and one patient had clinical disease caused by Nocardia asteroides. The clinical outcome varies from case to case, since five patients (aged 2-11 years) died of overwhelming infection, whereas eight patients (aged 3-12 years) are still in good health and are not currently taking antibiotics. In conclusion, IL12 deficiency is not limited to a single kindred, shows significant variability of outcome, and should be considered in the genetic diagnosis of patients with mycobacteriosis and/or salmonellosis. To date, two founder IL12B mutations have been identified, accounting for the recurrence of a large deletion and a small insertion within populations from the Indian subcontinent and from the Arabian Peninsula, respectively.

journal_name

Am J Hum Genet

authors

Picard C,Fieschi C,Altare F,Al-Jumaah S,Al-Hajjar S,Feinberg J,Dupuis S,Soudais C,Al-Mohsen IZ,Génin E,Lammas D,Kumararatne DS,Leclerc T,Rafii A,Frayha H,Murugasu B,Wah LB,Sinniah R,Loubser M,Okamoto E,Al-Ghonaium

doi

10.1086/338625

subject

Has Abstract

pub_date

2002-02-01 00:00:00

pages

336-48

issue

2

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(07)63949-4

journal_volume

70

pub_type

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