A novel SLC37A4 missense mutation in GSD-Ib without hepatomegaly causes enhanced leukocytes endoplasmic reticulum stress and apoptosis.

Background: Glycogen storage disease (GSD) type Ib is an autosomal recessive disease caused by defects of glucose-6-phosphate transporter (G6PT), encoded by the SLC37A4 gene. To date, over 100 mutations have been revealed in the SLC37A4 gene. GSD-Ib patients manifest a metabolic phenotype of impaired blood glucose homeostasis and also carry the additional complications of neutropenia and myeloid dysfunction.

Methods: Here, we present two daughters with an initial diagnosis of gout in a Chinese consanguineous family. Whole-exome sequencing was performed to identify the mutations. The mechanism of leukocytopenia was investigated.

Results: Whole-exome sequencing analysis of the proband identified a novel homozygous p.P119L mutation in SLC37A4, leading to a diagnosis of GSD-Ib. We found that the potential pathogenic p.P119L mutation leads to an unusual phenotype characterized by gout at onset, and GSD-Ib arising from this variant also manifests multiple metabolic abnormalities, leukocytopenia, and anemia, but no hepatomegaly. The leukocytes from the proband showed increased mRNA levels of sXBP-1, BIP, and CHOP genes in the unfolded protein response pathway, and enhanced Bax mRNA and caspase-3 activity, which might contribute to leukocytopenia.

Conclusion: Our findings broaden the variation spectrum of SLC37A4 and suggest no strict genotype-phenotype correlations in GSD-Ib patients.