A compound heterozygous mutation in GPD1 causes hepatomegaly, steatohepatitis, and hypertriglyceridemia

Abstract

The constellation of clinico-pathological and laboratory findings including massive hepatomegaly, steatosis, and marked hypertriglyceridemia in infancy is extremely rare. We describe a child who is presented with the above findings, and despite extensive diagnostic testing no cause could be identified. Whole exome sequencing was performed on the patient and parents' DNA. Mutations in GPD1 encoding glycerol-3-phosphate dehydrogenase that catalyzes the reversible redox reaction of dihydroxyacetone phosphate and NADH to glycerol-3-phosphate (G3P) and NAD þ were identified. The proband inherited a GPD1 deletion from the father determined using copy number analysis and a missense change p.(R229Q) from the mother. GPD1 protein was absent in the patient's liver biopsy on western blot. Low normal activity of carnitine palmitoyl transferases, CPT1 and CPT2, was present in the patient's skin fibroblasts, without mutations in genes encoding for these proteins. This is the first report of compound heterozygous mutations in GPD1 associated with a lack of GPD1 protein and reduction in CPT1 and CPT2 activity.

Expanding the molecular diversity and phenotypic spectrum of glycerol 3‐phosphate dehydrogenase 1 deficiency

“…GPD1 deficiency may affect lipid homeostasis causing relative excess of DHAP and reduction of G3P, as observed in liver, muscle, and kidney of the mouse model of GPD1 deficiency (MacDonald and Marshall 2000). Furthermore, to explain the clinical phenotype it has been hypothesized that the excess DHAP may activate the peroxysomal pathway of DHAP acylation (Joshi et al 2014).…”

“…These patients presented with hepatomegaly, hepatic steatosis and hypertriglyceridemia, during the first year of life, and were found homozygous for GPD1 splicing mutation, c.361-1G > C (Basel-Vanagaite et al 2012). More recently, an additional affected female patient of Caucasian descent, who presented with early-onset severe hepatomegaly, failure to thrive, vomiting, fatty liver and hypertriglyceridemia, was found by whole exome sequencing (WES) to be a compound heterozygote for a maternally transmitted c.686G > A missense mutation (p.R229Q) and a paternally inherited large deletion encompassing GPD1 or part of its coding region (Joshi et al 2014).…”

“…The disease manifests in early infancy with transient hypertriglyceridemia, hepatomegaly, elevated liver enzymes, fatty liver and hepatic fibrosis, and has been associated with biallelic inactivating mutations in the GPD1 gene (Basel-Vanagaite et al 2012;Joshi et al 2014). Located on chromosome 12q13.12, GPD1 encodes glycerol-3-phosphate dehydrogenase 1, a cytosolic protein that catalyzes the reversible redox reaction of dihydroxyacetone phosphate (DHAP) and reduced nicotine adenine dinucleotide (NADH) to glycerol-3-phosphate (G3P) and NAD + , playing a critical role in both carbohydrate and lipid metabolism.…”

Inborn errors of cytoplasmic triglyceride metabolism

“…Deficiency of glycerol-3-phosphate dehydrogenase 1 (GPD1, cytoplasmic GPD) Humans Basel-Vanagaite et al (Basel-Vanagaite et al 2012) described ten individuals from an Israeli Arab geographic isolate and Joshi et al (Joshi et al 2014) reported one patient (designated here as patient 11); patients 1-10 are homozygous for a splicing mutation in GPD1 predicted to cause premature termination and patient 11 is a genetic compound with no detectable GPD1 protein in liver.…”

An overview of inborn errors of complex lipid biosynthesis and remodelling

“…GA3P is further metabolized to dihydroxyacetone phosphate (DHAP) and glycerol 3phosphate through triose phosphate isomerase (TPI) and glycerol 3-phosphate dehydrogenase (GPD), respectively. Mutations in the gene GPD1 result in a severe liver dysfunction with liver steatosis and fibrosis associated with a paradoxical transient infantile hypertriglyceridemia (Basel-Vanagaite et al 2012; Joshi et al 2014; Mitchell in this issue). Citrate also activates acetyl-CoA carboxylase (ACC) for malonyl-CoA synthesis.…”