Transient Infantile Hypertriglyceridemia, Fatty Liver, and Hepatic Fibrosis Caused by Mutated GPD1, Encoding Glycerol-3-Phosphate Dehydrogenase 1 Lina.

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Transient Infantile Hypertriglyceridemia, Fatty Liver, and Hepatic Fibrosis Caused by Mutated GPD1, Encoding Glycerol-3-Phosphate Dehydrogenase 1 Lina Basel-Vanagaite, Noam Zevit, Adi Har Zahav, Liang Guo, Saj Parathath, Metsada Pasmanik-Chor, Adam D. McIntyre, Jian Wang, Adi Albin-Kaplanski, Corina Hartman, Daphna Marom, Avraham Zeharia, Abir Badir, Oded Shoerman, Amos J. Simon, Gideon Rechavi, Mordechai Shohat, Robert A. Hegele, Edward A. Fisher, Raanan Shamir The American Journal of Human Genetics Volume 90, Issue 1, Pages 49-60 (January 2012) DOI: 10.1016/j.ajhg.2011.11.028 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Family Tree, Candidate Region, and Mutation Analysis (A) Pedigrees of the families and segregation analysis of the mutation. Segregation was assayed by PCR amplification of the genomic DNA and restriction by DdeI. The mutation eliminates a DdeI restriction site, which digests the 362 bp fragment into 11, 119, and 232 bp fragments, compared to a control sample, which digests into 11, 17, 119, and 215 bp. Blackened symbols represent affected individuals. (B) Homozygosity region as defined by Homozygosity Mapper. Red lines represent the homozygosity region common to individuals F2-III1 and F1-IV4. (C) Candidate region (only OMIM genes listed). (D) Mutation analysis of GPD1. Sequence chromatogram from wild-type (WT), carrier (C), and affected (M) genotypes on genomic DNA and cDNA. The American Journal of Human Genetics 2012 90, 49-60DOI: (10.1016/j.ajhg.2011.11.028) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Liver Biopsies and Ultrasound (A and B) Affected individuals F1-IV2 at 2.4 years of age: Trucut liver biopsy. (A) The liver parenchyma shows macro- and microvesicular fatty change and mild mononuclear inflammatory infiltrate in the portal spaces. Hematoxylin and eosin staining (H&E), magnification 10×. (B) Widening of the portal spaces because of fibrotic deposition with septal formation. Masson trichrome stain, magnification 10×. (C and D) Affected individual F1-IV4 at 4.5 years of age: Trucut liver biopsy. (C) Liver parenchyma shows fatty change, both macro- and microvesicular, and small collections of inflammatory cells, including lymphocytes, histiocytes, polymorphonuclears, and eosinophils. H&E, magnification 10×. (D) Portal fibrosis with septal formation and mild sinusoidal fibrosis. Masson Trichrome stain, magnification 10×. (E) Ultrasound of affected individual F1-IV4 at 11.9 years of age demonstrates diffuse hyperechogenicity of the liver with a fine granular pattern. In comparison, the kidney parenchyma (K) appears hypoechoic. (F) Ultrasound of another affected individual at 3 months of age showing dense diffuse hyperechogenicity of the liver with loss of imaging of the portal areas. The American Journal of Human Genetics 2012 90, 49-60DOI: (10.1016/j.ajhg.2011.11.028) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 cDNA Analysis of Splice-Site Modification in an Affected Individual and Control Splice-site mutation eliminating the exon 4 splice site and creating a shorter protein by translation continuation from the mutation site until a stop codon in-frame. The American Journal of Human Genetics 2012 90, 49-60DOI: (10.1016/j.ajhg.2011.11.028) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 4 GPD1 Gene Evolutionary Conservation and Protein Structure (A) GPD1 gene evolutionary conservation presented by ECR browser. Sequence conservation of exons (blue) and introns (orange), as well as UTR (yellow) and repeats (green) can be visualized. Layer height presents % identity of sequence pairwise alignment, asterisk and red vertical line represent the location of the mutation. (B) Protein “wiring diagram” of GPD1. This schematic plot provides sequence, secondary structure elements, domains and motifs. The splicing point is marked on the protein's secondary structure (red asterisk). The protein sequence is colored by conservation (high sequence conservation is marked in red, low conservation in blue). Secondary structures (helices (H1-H18) and strands) are marked in purple. Legend key presents motifs, patterns and active sites (colored triangles) on the protein. (C) GPD1 Domains. Two GPD1 Domains from Pfam are shown. The mutation is marked by a red asterisk. The American Journal of Human Genetics 2012 90, 49-60DOI: (10.1016/j.ajhg.2011.11.028) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 5 Intracellular and Secreted TG and Total Cholesterol Concentration in HepG2 Cells Overexpressing Wild-Type and Mutant GPD1 cDNA (A) Total cholesterol content in wild-type and mutant GPD1 overexpressing Hep2G cells. (B) TG content in wild-type and mutant GPD1 overexpressing HepG2 cells. (C) TG accumulation in medium in wild-type and mutant GPD1 overexpressing HepG2 cells. Error bars represent standard error of the mean. The American Journal of Human Genetics 2012 90, 49-60DOI: (10.1016/j.ajhg.2011.11.028) Copyright © 2012 The American Society of Human Genetics Terms and Conditions