Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome biogenesis disorders (PBDs) are severe autosomal recessive neurological diseases caused by a defect of peroxisomal assembly factors. Zellweger syndrome, the most severe phenotype, is characterized by hypotonia, psychomotor retardation and neuronal migration disorder. Neonatal adrenoleukodystrophy and infantile Refsum disease are milder phenotypes of this disease. Thirteen complementation groups have been established since the genetic heterogeneity of PBDs was elucidated in 1988. Eleven genes for PBDs have been identified either by a functional complementation cloning or by EST homology searches. In 1992, the first gene for PBDs, PEX2, was identified. It encodes peroxisomal integral membrane protein with a RING finger domain. PEX5 and PEX7 are the genes for peroxisomal targeting signal (PTS)-1 and -2 receptors, respectively. PEX3, PEX16 and PEX19 are considered to be required for the early stage of peroxisome biogenesis. PEX13 protein has an SH3 docking site that binds to the PTS-1 receptor. PEX1 and PEX6 encode ABC protein, and PEX10 and PEX12 also encode integral membrane protein, with RING finger. Temperature-sensitivity, whereby peroxisomal biogenesis and metabolic dysfunctions are restored at 30 degrees C in cells from mild phenotypes, is a useful event for predicting the clinical severity and for elucidation of peroxisome biogenesis. Investigations using knockout mice are expected to facilitate understanding of migration disorders.
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PMID:Clinical, biochemical and genetic aspects and neuronal migration in peroxisome biogenesis disorders. 1140 37

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.
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PMID: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. 1753 73

At least 14 distinctive PEX genes function in the biogenesis of peroxisomes. Biallelic alterations in the peroxisomal biogenesis factor 12 (PEX12) gene lead to Zellweger syndrome spectrum (ZSS) with variable clinical expressivity ranging from early lethality to mildly affected with long-term survival. Herein, we define 20 patients derived from 14 unrelated Egyptian families, 19 of which show a homozygous PEX12 in-frame (c.1047_1049del p.(Gln349del)) deletion. This founder mutation, reported rarely outside of Egypt, was associated with a uniformly severe phenotype. Patients showed developmental delay in early life followed by motor and mental regression, progressive hypotonia, unsteadiness, and lack of speech. Seventeen patients had sparse hair or partial alopecia, a striking feature that was not noted previously in PEX12. Neonatal cholestasis was manifested in 2 siblings. Neurodiagnostics showed consistent cerebellar atrophy and variable white matter demyelination, axonal neuropathy in about half, and cardiomyopathy in 10% of patients. A single patient with a compound heterozygous PEX12 mutation exhibited milder features with late childhood onset with gait disturbance and learning disability. Thus, the PEX12 relatively common founder mutation accounts for the majority of PEX12-related disease in Egypt and delineates a uniform clinical and radiographic phenotype.
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PMID:A founder mutation in PEX12 among Egyptian patients in peroxisomal biogenesis disorder. 3312 25