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Does The Phosphomannomutase pmm1 Functionally Compensate for Decreased pmm2 Expression in a Zebrafish model for PMM2‐CDG?
Author(s) -
Steet Richard Anthony,
Cline Abigail,
Gao Ningguo,
FlanaganSteet Heather,
Lehrman Mark
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.830.1
Subject(s) - zebrafish , enzyme , mannose , biology , glycosylation , biochemistry , microbiology and biotechnology , gene
Congenital Disorders of Glycosylation (CDGs) are rare diseases characterized by wide spectrum clinical abnormalities and impaired glycosylation. The most common CDG subtype, PMM2‐CDG, results from mutations in PMM2, which encodes the phosphomannomutase (pmm) enzyme that converts mannose‐6‐P (M6P) to mannose‐1‐P (M1P). We previously reported (Cline et al. 2012) a morpholino‐based PMM2‐CDG zebrafish model that exhibits defects consistent with PMM2‐CDG patients, including craniofacial defects and altered motor neurogenesis. In this model, pmm enzymatic activity could not be reduced below 30% of control, suggesting a second enzyme activity. Global N‐linked glycosylation and lipid‐linked oligosaccharide (LLO) levels were reduced, and the LLO deficiency was attributed to LLO destruction by accumulating M6P, the PMM2 substrate. Importantly, suppression of the M6P synthesizing enzyme, mannose phosphate isomerase, in the pmm2 background normalized M6P levels, partially rescued craniofacial defects, and abrogated pmm2‐dependent LLO cleavage. Here we investigate the expression and functional relevance of pmm1, a second enzyme reported to have pmm enzymatic activity. Overexpression of Pmm1 in pmm2 morphants increased net pmm activity two‐fold. Pmm1 expression also normalized biochemical and phenotypic parameters of pmm2 morphants.