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(+) 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.

Figure 1

Radio-pathologic and genetic findings in proband with GPD1 mutation. (a) Liver biopsy: the liver parenchyma shows macro- and microvesicular fatty change on Hematoxylin and Eosin staining (H&E), magnification × 10. (b and c) Ultrasound demonstrates diffuse hyperechogenicity of the liver with a fine granular pattern. In comparison, the gall bladder (GB) (b) and right kidney parenchyma (RK) (c) are hypoechoic. (d) DNA sequence analysis of genomic PCR products illustrates three genotypes for GPD1 c.686G>C seen in the family with proband homozygous, mother heterozygous and father WT for the allele. (e) Altered arginine residue (red) is evolutionarily well conserved in GPD1 and GPD1L proteins in vertebrates and lower organisms including yeast. (f) Relative GPD1 expression levels using copy number assay revealed father and proband to be GPD1 haploinsufficient relative to the mother and two controls.

Figure 2

Western blot analysis on liver biopsy sample from the proband and age-matched control. GPD1 protein was absent in the proband although similar amounts of GPD2 and CPT1A were present in the proband and control.