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| Ataxia - paediatric v0.318 | PIK3R5 |
Chirag Patel gene: PIK3R5 was added gene: PIK3R5 was added to Ataxia - paediatric. Sources: Literature Mode of inheritance for gene: PIK3R5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIK3R5 were set to PubMed: 22065524 Phenotypes for gene: PIK3R5 were set to Ataxia-oculomotor apraxia 3, OMIM #615217 Review for gene: PIK3R5 was set to RED Added comment: Al Tassan et al. (2012) reported 4 sibs, from consanguineous Saudi Arabian family, with ataxia-oculomotor apraxia. The proband developed progressive unsteady gait and had frequent falls at age 14 years with later onset of arm dysmetria and dysarthria. He became wheelchair-bound at age 23. Ocular movement was impaired, with slowed saccadic eye movements and head-eye lag resulting in head thrust, but smooth pursuit was normal. He had severe limb and axial dysmetria with mild distal atrophy and weakness affecting the lower limbs more than the upper limbs. He also had distal sensory impairment, more prominent in the lower limbs, areflexia, and axonal sensory polyneuropathy with absent sensory nerve action potentials in the lower limbs. Laboratory studies showed increased level of alpha-fetoprotein, and brain MRI showed atrophy of the cerebellar folia and vermis. His 3 sibs were similarly affected. A homozygous mutation in the PIK3R5 gene (P629S) was found by linkage analysis followed by sequencing of the genes within the region. Sources: Literature |
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| Ataxia - paediatric v0.290 | RNF220 |
Zornitza Stark gene: RNF220 was added gene: RNF220 was added to Ataxia - paediatric. Sources: Literature founder tags were added to gene: RNF220. Mode of inheritance for gene: RNF220 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RNF220 were set to 33964137; 10881263 Phenotypes for gene: RNF220 were set to Leukodystrophy; CNS hypomyelination; Ataxia; Intellectual disability; Sensorineural hearing impairment; Elevated hepatic transaminases; Hepatic fibrosis; Dilated cardiomyopathy; Spastic paraplegia; Dysarthria; Abnormality of the corpus callosum Review for gene: RNF220 was set to GREEN Added comment: Sferra et al (2021 - PMID: 33964137) provide extensive evidence that biallelic RNF220 mutations cause a disorder characterized by hypomyelinating leukodystrophy, ataxia (9/9 - onset 1-5y), borderline intellectual functioning (3/9) / intellectual disability (5/9 - in most cases mild), sensorineural deafness (9/9) with complete hearing loss in the first decade of life, hepatopathy (9/9) with associated periportal fibrosis, and dilated cardiomyopathy (9/9) which was fatal. Other neurologic manifestations apart from ataxia incl. hyperreflexia (8/8), spastic paraplegia (9/9), dysarthria (9/9), peripheral neuropathy (4/9), seizures in one case (1/9). Upon brain MRI there was thin corpus callosum (9/9) or cerebellar atrophy in some (2/9). The authors identified homozygosity for 2 recurrent missense RNF220 variants in affected members belonging to these 5 broad consanguineous pedigrees (7 families), namely NM_018150.4:c.1094G>A / p.Arg365Gly in 4 Roma families in the context of a shared haplotype (/founder effect) as well as c.1088G>A / p.Arg363Gly in a large pedigree from southern Italy initially reported by Leuzzi et al (2000 - PMID: 10881263). Extensive segregation analyses were carried out including several affected and unaffected members. RNF220 encodes ring finger protein 220, which functions as an E3 ubiquitin ligase. Previous studies have shown among others a role in modulation of Sonic hedgehog/GLI signaling and cerebellar development Evidence for the role of RNF220 included relevant expression, localization within the cell, interaction partners (lamin B1, 20S proteasome), similarities with other laminopathies in terms of phenotype, etc : *RNF220 has a relevant expression pattern in CNS (based on qRT-PCR analyses in human brain, cerebellum, cerebral cortex / mRNA levels in human fetal CNS with higher expression in cerebellum, spinal cord and cortex / previous GTEx data / protein levels in mouse CNS) *The protein displays nuclear localization based on iPSC cells differentiated to motor neurons (also supported by data from the Human Protein Atlas). Transfection of COS-1 cells demonstrated localization primarily to the nucleus (as also previously demonstrated in HEK293T cells) in vesicle like structures with ASF2/SF2 colocalization suggesting enrichment in nuclear speckles. There was also partial co-distribution with the 20S proteasome. R363Q and R365Q additionally coalesced in the cytoplasm forming protein aggregates/inclusions. *Immunofluorescence studies in patient fibroblasts also confirmed abnormal increase of the protein in the cytoplasm and increased fluorescence with the 20S proteasome. *Proteomic identification of RNF220-interacting proteins in transfected HEK293T cells demonstrated enrichment for all members of the lamin protein family (incl . lamin B1, AC, B2). *RNAi-mediated downregulation of RNF222 in Drosophila suggested altered subcellular localization and accumulation of the fly orthologue for human lamin B1. *Immunoprecipitation of lamin B1 from the nuclear matrix of cerebellar cells suggested significant interaction of endogenous lamin B1 with RNF220, while transfection studies in HEK293T cells for wt/mt suggested reduced binding to endogenous lamin B1 for RNF220 mt compared to wt (more prominent for R365Q). RNF220 mutants also reduced ubiquitination of nuclear lamin B1 compared to wt. *Patient fibroblasts immunostained with different nuclear envelope markers displayed abnormal nuclear shapes with multiple invaginations and lobulations, findings also observed in laminopathies. Sources: Literature |
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| Ataxia - paediatric v0.288 | PRDX3 |
Zornitza Stark gene: PRDX3 was added gene: PRDX3 was added to Ataxia - paediatric. Sources: Literature Mode of inheritance for gene: PRDX3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRDX3 were set to 33889951 Phenotypes for gene: PRDX3 were set to Cerebellar ataxia (early onset, mild to moderate, progressive) Review for gene: PRDX3 was set to GREEN Added comment: Biallelic variants in 5 unrelated families with early onset (median 21 years , range 13-22 years) with ataxia with variable additional hyper- and hypokinetic movement disorders, and severe early-onset cerebellar atrophy (seen on MRI), and involvement of the brainstem, medullary olive and parietal cortex. Evolution of the disease was gait ataxia leading to upper limb ataxia, then dysarthria and then dysphagia, all within a decade. For some of these patients, the phenotype included myoclonus, dystonia and / or tremor. Mild classical mitochondrial features were seen in one of the patients, namely ptosis and COX-negative fibres. The variants were homozygous nonsense, homozygous frameshift, homozygous missense, and a compound heterozygote with a splice variant and missense, all leading to complete loss of the protein. Oxidative stress and mitochondrial dysfunction was indicated as the disease mechanism. The families originated from Germany, France, India and two from eastern Turkey. The two families from Turkey were seemingly unrelated to each other but had the same homozygous missense. Patient fibroblasts from each of the five probands showed lack of protein (via Western blot) and decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity. PRDX3 encodes peroxiredoxin 3, a mitochondrial antioxidant protein, that catalyses the reduction of hydrogen peroxide. It localises in the mitochondria, where most hydrogen peroxide is generated. Functional studies: PRDX3 knockdown (induced by silencing RNA against PRDX3) in cerebellar medulloblastoma cells showed significantly decreased cell viability, increased hydrogen peroxide levels and increased susceptibility to apoptosis triggered by reactive oxygen species. In addition, induced knockdown drosophila (in vivo animal model) had aberrant locomotor phenotypes and reduced lifespans, while immunolabelling of the brain showed increased cell death after exposure to oxidative stress. Sources: Literature |
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| Ataxia - paediatric v0.262 | CAD | Zornitza Stark Marked gene: CAD as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia - paediatric v0.262 | CAD | Zornitza Stark Gene: cad has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia - paediatric v0.262 | CAD | Chirag Patel Classified gene: CAD as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia - paediatric v0.262 | CAD | Chirag Patel Gene: cad has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia - paediatric v0.261 | CAD |
Chirag Patel gene: CAD was added gene: CAD was added to Ataxia - paediatric. Sources: Literature Mode of inheritance for gene: CAD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CAD were set to PMID: 32820246 Phenotypes for gene: CAD were set to Epileptic encephalopathy, early infantile, 50; OMIM # 616457 Review for gene: CAD was set to GREEN gene: CAD was marked as current diagnostic Added comment: 2020 series: 6/20 patients reported had ataxia relating to cerebellar atrophy, which is an expansion to the phenotype. Sources: Literature |
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| Ataxia - paediatric v0.93 | COA7 |
Bryony Thompson gene: COA7 was added gene: COA7 was added to Ataxia - paediatric. Sources: Expert list Mode of inheritance for gene: COA7 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: COA7 were set to Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3 MIM#618387 Review for gene: COA7 was set to GREEN Added comment: Onset usually in the first decade. Sources: Expert list |
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| Ataxia - paediatric v0.66 | TMEM240 |
Zornitza Stark gene: TMEM240 was added gene: TMEM240 was added to Ataxia - paediatric. Sources: Expert list Mode of inheritance for gene: TMEM240 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TMEM240 were set to 25070513 Phenotypes for gene: TMEM240 were set to Spinocerebellar ataxia 21, MIM# 607454 Review for gene: TMEM240 was set to GREEN Added comment: At least 8 unrelated families reported. Onset in the first decades of life, including in childhood, of slowly progressive cerebellar ataxia, which is associated with cognitive impairment in most patients Sources: Expert list |
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