A novel PEX12 mutation identified as the cause of a peroxisomal biogenesis disorder with mild clinical phenotype, mild biochemical abnormalities in fibroblasts and a mosaic catalase immunofluorescence pattern, even at 40 degrees C.
Mutations in 12 different PEX genes can cause a generalized peroxisomal biogenesis disorder with clinical phenotypes ranging from Zellweger syndrome to infantile Refsum disease. To identify the specific PEX gene to be sequenced, complementation analysis is first performed in fibroblasts using catalase immunofluorescence. A patient with a relatively mild phenotype of infantile cholestasis, hypotonia and motor delay had elevated plasma very long-chain fatty acids and bile acid precursors, but fibroblast studies revealed normal or only mildly abnormal peroxisomal parameters and mosaic catalase immunofluorescence. This mosaicism persisted even when the incubation temperature was increased from 37 degrees C to 40 degrees C, a maneuver previously shown to abolish mosaicism by exacerbating peroxisomal dysfunction. As mosaicism precludes complementation analysis, a candidate gene approach was employed. After PEX1 sequencing was unrewarding, PEX12 sequencing revealed homozygosity for a novel c.102A>T (p.R34S) missense mutation affecting a partially conserved residue in the N-terminal region important for localization to peroxisomes. Transfection of patient fibroblasts with wild-type PEX12 cDNA confirmed that a PEX12 defect was the basis for the PBD. Homozygosity for c.102A>T was identified in a second patient of similar ethnic origin also presenting with a mild phenotype. PEX12 is a highly probable candidate gene for direct sequencing in the context of a mild clinical phenotype with mosaicism and minimally abnormal peroxisomal parameters in fibroblasts.
Zeharia
Avraham
A
Day Hospitalization Unit, Schneider Children's Medical Center of Israel, Sackler School of Medicine, Tel Aviv University, Petach Tikvah, Israel.
Ebberink
Merel S
MS
Departments of Clinical Chemistry and Pediatrics, Academic Medical Centre, Emma Children's Hospital, University of Amsterdam, Amsterdam, The Netherlands.
Wanders
Ronald J A
RJA
Departments of Clinical Chemistry and Pediatrics, Academic Medical Centre, Emma Children's Hospital, University of Amsterdam, Amsterdam, The Netherlands.
Waterham
Hans R
HR
Departments of Clinical Chemistry and Pediatrics, Academic Medical Centre, Emma Children's Hospital, University of Amsterdam, Amsterdam, The Netherlands.
Gutman
Alisa
A
Department of Clinical Biochemistry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Nissenkorn
Andreea
A
Pediatric Neurology Unit, Safra Children's Hosptial, Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Hashomer, Israel.
Korman
Stanley H
SH
Department of Clinical Biochemistry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. korman@hadassah.org.il.|Metabolic Diseases Unit, Division of Pediatrics, Hadassah-Hebrew University Medical Center, POB 12000, Jerusalem, Israel. korman@hadassah.org.il.
D002374:Catalase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002675:Child, Preschool; D002779:Cholestasis / Q000235:genetics / Q000473:pathology; D005347:Fibroblasts / Q000737:chemistry* / Q000378:metabolism* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006358:Hot Temperature; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009030:Mosaicism; D020675:Peroxisomes / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D052919:Refsum Disease, Infantile / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism
D008565:Membrane Proteins; C105251:PEX12 protein, human; D002374:Catalase