Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels.
J Allergy Clin Immunol
; 133(5): 1410-9, 1419.e1-13, 2014 May.
Article
em En
| MEDLINE
| ID: mdl-24698316
ABSTRACT
BACKGROUND:
Recurrent bacterial and fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES. One crucial enzyme in the glycosylation pathway is phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of uridine diphosphate N-acetylglucosamine, which is required for the biosynthesis of N-glycans.OBJECTIVE:
We sought to elucidate the genetic cause in patients with HIES who do not carry mutations in STAT3 or DOCK8.METHODS:
After establishing a linkage interval by means of SNPchip genotyping and homozygosity mapping in 2 families with HIES from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by means of Western blotting, and glycosylation was profiled by using mass spectrometry.RESULTS:
Mutational analysis of candidate genes in an 11.9-Mb linkage region on chromosome 6 shared by 2 multiplex families identified 2 homozygous mutations in PGM3 that segregated with disease status and followed recessive inheritance. The mutations predict amino acid changes in PGM3 (p.Glu340del and p.Leu83Ser). A third homozygous mutation (p.Asp502Tyr) and the p.Leu83Ser variant were identified in 2 other affected families, respectively. These hypomorphic mutations have an effect on the biosynthetic reactions involving uridine diphosphate N-acetylglucosamine. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-antennary and tetra-antennary N-glycans. T-cell proliferation and differentiation were impaired in patients. Most patients had developmental delay, and many had psychomotor retardation.CONCLUSION:
Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity because biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Fosfoglucomutase
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Cromossomos Humanos Par 6
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Imunoglobulina E
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Mutação de Sentido Incorreto
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Doenças Genéticas Inatas
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Homozigoto
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Imunidade
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Síndrome de Job
Tipo de estudo:
Clinical_trials
Limite:
Adult
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Child
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Female
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Humans
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Infant
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Male
País como assunto:
Africa
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article