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SLC37A4
solute carrier family 37 member 4
SLC37A4 is located on the long (q) arm of chromosome 11, at band 11q23.3. Arm ratio per GRCh38 - banding schematic.
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Clinical tests that include this
Overview
SLC37A4 encodes glucose-6-phosphate translocase, a membrane transport protein that plays a fundamental role in glucose homeostasis. This transporter works in partnership with the glucose-6-phosphatase enzyme to enable the final step in glucose production from stored glycogen and other precursors.
The protein is particularly important during fasting periods, when the body must generate glucose internally rather than obtain it from food. Pathogenic variants in SLC37A4 follow an autosomal recessive inheritance pattern, meaning two altered gene copies are required to cause disease. The primary condition associated with this gene is glycogen storage disease type Ib, a metabolic disorder affecting glucose regulation and immune function.
What the gene does
Glucose-6-phosphate translocase acts as a specialised transport channel embedded within the endoplasmic reticulum membrane, a network of internal cellular compartments involved in protein processing. The transporter's essential task is shuttling glucose-6-phosphate molecules across this membrane barrier, moving them from the cytoplasm into the endoplasmic reticulum's interior space.
Within the endoplasmic reticulum, the glucose-6-phosphate molecule encounters the glucose-6-phosphatase enzyme. This enzyme cleaves off the phosphate group, yielding free glucose molecules that can exit the cell and circulate in the bloodstream, supporting blood sugar stability when dietary intake is absent. The translocase therefore represents the critical first component in a coupled enzymatic system for generating usable glucose.
This metabolic process operates most actively in hepatic and renal tissues, organs that shoulder much of the responsibility for glucose production during inter-meal intervals. When glucose-6-phosphate translocase function is lost, glucose-6-phosphate molecules become trapped in the cytoplasm and remain inaccessible to the phosphatase enzyme, preventing glucose liberation regardless of available glycogen stores.
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Chromosome location
SLC37A4 is located on the long arm of chromosome 11 at position 23.3, designated as 11q23.3. This chromosomal region contains numerous genes involved in metabolic and developmental processes. The gene structure and precise exon organisation have been characterised through genomic sequencing studies.
Protein structure
Experimental characterisation of detailed domain architecture remains limited for this protein. The glucose-6-phosphate translocase comprises 429 amino acids and is predicted to contain multiple transmembrane segments that span the endoplasmic reticulum membrane, forming a channel through which glucose-6-phosphate molecules can pass. These membrane-spanning regions create the structural basis for the protein's transport function, positioning specific amino acid residues to recognise and bind the substrate molecule.
Key variants
More than 80 pathogenic variants in SLC37A4 have been identified in individuals with glycogen storage disease type Ib. Most documented pathogenic changes involve single nucleotide substitutions that result in amino acid replacements, compromising the transporter's substrate recognition or structural integrity. Some variants affect the protein's stability or prevent it from being correctly positioned in the endoplasmic reticulum membrane. The spectrum and frequency of variants can differ across populations.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Pathogenic variants in SLC37A4 cause glycogen storage disease type Ib, a rare inherited metabolic disorder characterised by the body's inability to maintain adequate blood glucose levels during fasting. Affected individuals experience hypoglycaemia, accumulation of glycogen and fat in the liver leading to hepatomegaly, and growth delays.
A distinguishing feature of type Ib, compared to the closely related type Ia caused by G6PC variants, is the presence of recurrent infections and inflammatory bowel symptoms. Research suggests this occurs because the glucose-6-phosphate transport defect also impairs neutrophil function, affecting the immune system's ability to combat bacterial infections.
Inheritance pattern
Conditions caused by pathogenic SLC37A4 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
SLC37A4 appears on multiple NHS Genomic Medicine Service panels as a gene with established clinical validity. It holds green classification status on the Glycogen storage disease panel (R274) and the Likely inborn error of metabolism panel (R98), indicating strong evidence for its role in these conditions. The gene is also included on panels for Primary immunodeficiency or monogenic inflammatory bowel disease (R15), reflecting the immune manifestations observed in glycogen storage disease type Ib. Additional memberships include the Congenital disorders of glycosylation panel, Gastrointestinal epithelial barrier disorders panel, Infantile enterocolitis and monogenic inflammatory bowel disease panel, Ketotic hypoglycaemia panel, and Undiagnosed metabolic disorders panel.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the difference between glycogen storage disease type Ia and type Ib?
Both types impair the final step of glucose production, but type Ia results from variants in G6PC (the enzyme), while type Ib stems from variants in SLC37A4 (the transporter). Type Ib distinctively includes immune dysfunction with recurrent infections and inflammatory bowel symptoms, which are typically absent in type Ia.
How is SLC37A4 inherited?
SLC37A4-related conditions follow autosomal recessive inheritance, meaning an individual must inherit a pathogenic variant from both parents to develop glycogen storage disease type Ib. Carriers with one altered copy typically do not show symptoms.
Why does SLC37A4 deficiency affect the immune system?
Research indicates that neutrophils, a type of white blood cell, require functional glucose-6-phosphate transport for optimal energy metabolism and cellular processes. When this transport is impaired, neutrophil function becomes compromised, leading to increased susceptibility to bacterial infections.
References
- Chou JY, Jun HS, Mansfield BC. Neutropenia in type Ib glycogen storage disease. Current opinion in hematology. 2010. PMID: 19741523
- Melis D, Fulceri R, Parenti G. Genotype/phenotype correlation in glycogen storage disease type 1b: a multicentre study and review of the literature. European journal of pediatrics. 2005. PMID: 15906092
- van Schaftingen E, Gerin I. The glucose-6-phosphatase system. The Biochemical journal. 2002. PMID: 11879177
- Matern D, Seydewitz HH, Bali D. Glycogen storage disease type I: diagnosis and phenotype/genotype correlation. European journal of pediatrics. 2002. PMID: 12373566