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Eleven percent intact PGM3 in a severely immunodeficient patient with a novel splice-site mutation, a case report
Karolinska Inst, Dept Lab Med, Clin Res Ctr, Novum, SE-14186 Stockholm, Sweden..
Karolinska Inst, Dept Lab Med, Clin Res Ctr, Novum, SE-14186 Stockholm, Sweden..
Karolinska Inst, Dept Lab Med, Clin Res Ctr, Novum, SE-14186 Stockholm, Sweden.;Hawler Med Univ, Coll Pharm, Dept Clin Anal, Erbil, Kurdistan Regio, Iraq..
Karolinska Univ Hosp, Dept Clin Immunol, SE-14186 Stockholm, Sweden..
Vise andre og tillknytning
2018 (engelsk)Inngår i: BMC Pediatrics, ISSN 1471-2431, E-ISSN 1471-2431, Vol. 18, artikkel-id 285Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Background: A novel immunodeficiency, frequently accompanied by high serum-IgE, and caused by mutations in the PGM3 gene was described in 2014. To date there are no unique phenotype characteristics for PGM3 deficiency. PGM3 encodes a carbohydrate-modifying enzyme, phosphoglucomutase 3. Null-mutations are quite likely lethal, and to date only missense mutations or small deletions have been reported. Such mutations frequently cause a combination of reduced enzyme activity and protein instability, complicating determination of the enzyme level needed for survival. Here we present the first patient with a homozygous splice-modifying mutation in the PGM3 gene. An A > G substitution at position c.871 +3 (transcript NM_001199917) is causing a deletion of exon 7 in the majority of PGM3 transcripts. In addition, this case further increases the clinical phenotypes of immunodeficiency caused by PGM3 mutations. Case presentation: We describe the symptoms of a 3-year-old girl who was severely growth retarded, had vascular malformations, extensive eczema, multiple food-allergies, and was prone to infections. Unlike the majority of reported PGM3 deficient patients she lacked skeletal dysplasia and had normal neurocognitive development. In addition to the high serum-IgE, she displayed altered T cell numbers with reduced naive CD4(+) and CD8(+) T-cells, increased number of activated effector memory CD8(+) T cells and aberrant T-cell functions. The patient was homozygous for a new hypomorphic, splice-modifying mutation in the PGM3 gene, causing severely reduced mRNA levels. In the patient's cells, we observed 5% intact mRNA and approximately 11% of the protein levels seen in healthy controls. Treatment with allogeneic hematopoietic stem cell therapy was planned, but unfortunately the clinical condition deteriorated with multi-organ failure, which led to her death at 3 years of age. Conclusions: There is still no specific phenotype identified that distinguishes immunodeficiency caused by PGM3 mutations from other forms of immunodeficiency. The patient described here yields new information on the phenotypic variability among these patients. In addition, since all the synthesized protein is wild-type, it is possible for the first time to estimate the enzyme activity in vivo. The results suggest that1/10 of the normal PGM3 level is sufficient for survival but that it is insufficient for accurate carbohydrate processing.

sted, utgiver, år, opplag, sider
Springer, 2018. Vol. 18, artikkel-id 285
Emneord [en]
Congenital disorder of glycosylation, Hyper-IgE, N-acetylglucosamine-phosphate mutase, PGM3 enzyme activity, Phosphoglucomutase 3, Primary immunodeficiency, Splice-modifying mutation
HSV kategori
Identifikatorer
URN: urn:nbn:se:kth:diva-234589DOI: 10.1186/s12887-018-1258-9ISI: 000443127600001PubMedID: 30157810Scopus ID: 2-s2.0-85052577427OAI: oai:DiVA.org:kth-234589DiVA, id: diva2:1248359
Forskningsfinansiär
Swedish Cancer Society, CAN2013/389The Swedish Medical Association, K2015-68X-11247-21-3Swedish Association of Local Authorities and Regions, ALF-projects 2012006, ALFGBG-438361and ALFGBG-672451
Merknad

QC 20180914

Tilgjengelig fra: 2018-09-14 Laget: 2018-09-14 Sist oppdatert: 2018-09-14bibliografisk kontrollert

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