Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels.
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Sassi Atfa, Lazaroski Sandra, Wu Gang, Haslam Stuart M, Fliegauf Manfred, Mellouli Fethi, Patiroglu Turkan, Unal Ekrem, Ozdemir Mehmet Akif, Jouhadi Zineb, Khadir Khadija, Ben-Khemis Leila, Ben-Ali Meriem, Ben-Mustapha Imen, Borchani Lamia, Pfeifer Dietmar, Jakob Thilo, Khemiri Monia, Asplund A Charlotta, Gustafsson Manuela O, Lundin Karin E, Falk-Sörqvist Elin, Moens Lotte N, Gungor Hatice Eke, Engelhardt Karin R, Dziadzio Magdalena, Stauss Hans, Fleckenstein Bernhard, Meier Rebecca, Prayitno Khairunnadiya, Maul-Pavicic Andrea, Schaffer Sandra, Rakhmanov Mirzokhid, Henneke Philipp, Kraus Helene, Eibel Hermann, Kölsch Uwe, Nadifi Sellama, Nilsson Mats, Bejaoui Mohamed, Schäffer Alejandro A, Smith C I Edvard, Dell Anne, Barbouche Mohamed-Ridha, Grimbacher Bodo
Аннотация
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.