Mutation Update of<i>ARSA</i>and<i>PSAP</i>Genes Causing Metachromatic Leukodystrophy

Cesani, Martina; Lorioli, Laura; Grossi, Serena; Amico, Giulia; Fumagalli, Francesca; Spiga, Ivana; Filocamo, Mirella; Biffi, Alessandra

doi:10.1002/humu.22919

Cited by 106 publications

(111 citation statements)

References 124 publications

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“…More than 150 ARSA mutations have been described to date according to the Human Gene Mutation Database (HGMD; http://www.hgmd.cf.ac.uk/ac/index.php). In addition, rare mutations in the activator protein saposin B have also been described, which also cause MLD (Rafi et al, ; Zhang et al, ; Holtschmidt et al, ; Cesani et al, ). For late‐infantile MLD, the most common mutation is an ARSA splicing defect, c.465 + 1G > A, and for adult‐onset MLD the most common is c.1283C > T; together these mutations account for almost 33% of MLD alleles (Cesani et al, ).…”

Section: Geneticsmentioning

confidence: 99%

“…In addition, rare mutations in the activator protein saposin B have also been described, which also cause MLD (Rafi et al, ; Zhang et al, ; Holtschmidt et al, ; Cesani et al, ). For late‐infantile MLD, the most common mutation is an ARSA splicing defect, c.465 + 1G > A, and for adult‐onset MLD the most common is c.1283C > T; together these mutations account for almost 33% of MLD alleles (Cesani et al, ). Although data on genotype/phenotype correlations are limited, it is known that, if a subject is homozygous for mutations that do not make any functional ARSA, then they will have the severe late‐infantile form of the disease.…”

Section: Geneticsmentioning

confidence: 99%

“…The estimated incidence of MLD ranges from 1.4 to 1.8/100,000 live births (Gieselmann and Krageloh-Mann, 2010;Aubourg et al, 2011). Most subjects with MLD are of caucasian origin (Cesani et al, 2016). The arylsulfatase A gene is located on chromosome 22q13.33 (Narahara et al, 1992) and is alternatively spliced with eight or nine exons combining to produce three different mRNA species (Kreysing et al, 1990).…”

Section: Mldmentioning

confidence: 99%

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Gene therapy for metachromatic leukodystrophy

Rosenberg

Kaminsky

Aubourg

et al. 2016

J of Neuroscience Research

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Summary Leukodystrophies are rare white matter genetic disorders of the central nervous system (CNS) with progressive neurologic deterioration. One approach to the treatment of leukodystrophies is by gene therapy. Using metachromatic leukodystrophy (MLD), a leukodystrophy resulting from deficiency of a lysosomal catabolic enzyme arylsulfatase A (ARSA) as the example, this review is focused on the current status of preclinical and clinical development of gene therapy as a viable treatment option for leukodystrophies. In MLD, mutations in the ARSA gene result in excess buildup of sulfatides, which triggers apoptosis of glia and neurons. The disease is characterized by severe cerebral demyelination and atrophy, with progressive loss of oligodendrocytes, neurons and Schwann cells. The optimal therapy for MLD would provide persistent and high level expression of ARSA in the CNS. Gene therapy using adeno-associated virus (AAV) is an ideal choice for clinical development as it provides the best balance of potential for efficacy with a reduced safety risk profile. In this review, we have summarized preclinical data that support the use of a gene therapy with the AAVrh.10 serotype for clinical development as a treatment for MLD.

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Section: Geneticsmentioning

confidence: 99%

Section: Geneticsmentioning

confidence: 99%

Section: Mldmentioning

confidence: 99%

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Gene therapy for metachromatic leukodystrophy

Rosenberg

Kaminsky

Aubourg

et al. 2016

J of Neuroscience Research

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“…A number of leukoencephalopathies are inherited disorders with demyelination or defects of myelin biosynthesis and metabolism resulting in dysmyelination (Vanderver et al., ). In the last decade, the genetic etiology of several leukoencephalopathies such as metachromatic leukodystrophy, globoid cell leukodystrophy, and adrenoleukodystrophy has been elucidated (Cesani et al., ; Dubois‐Dalcq, Feigenbaum, & Aubourg, ; Husain, Altuwaijri, & Aldosari, ; Vanderver et al., ). Nevertheless, about half of leukoencephalopathies remain undiagnosed and unclassified specifically, which are worthy of further study (Zara et al., ).…”

Section: Introductionmentioning

confidence: 99%

Mutations inKARScause early-onset hearing loss and leukoencephalopathy: Potential pathogenic mechanism

Zhou

et al. 2017

Human Mutation

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Leukoencephalopathies are a broad class of common neurologic deterioration for which the etiology remains unsolved in many cases. In a Chinese Han family segregated with sensorineural hearing loss and leukoencephalopathy, candidate pathogenic variants were identified by targeted next-generation sequencing of 144 genes associated with deafness and 108 genes with leukoencephalopathy. Novel compound heterozygous mutations p.R477H and p.P505S were identified in KARS, which encodes lysyl-tRNA synthetase (LysRS), as the only candidate causative variants. These two mutations were functionally characterized by enzymatic assays, immunofluorescence, circular dichroism analysis, and gel filtration chromatography. Despite no alteration in the dimer-tetramer oligomerization and cellular distribution by either mutation, the protein structure was notably influenced by the R477H mutation, which subsequently released the protein from the multiple-synthetase complex (MSC). Mutant LysRSs with the R477H and P505S mutations had decreased tRNA aminoacylation and displayed a cumulative effect when introduced simultaneously. Our studies showed that mutations in KARS lead to a newly defined subtype of leukoencephalopathy associated with sensorineural hearing impairment. The combined effect of reduced aminoacylation and release of LysRS from the MSC likely underlies the pathogenesis of the KARS mutations identified in this study.

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“…To date 200 mutations have been described in the ARSA gene (4 In this study we constructed two missense (in exon 5 c.919G→A, p.307Glu→Lys and c.954G→T, p.318Trp→Cys) mutations by site-directed mutagenesis on wild-type ARSA gene, transiently transfected to the CHO cells, and characterized biochemically.…”

Section: Introductionmentioning

confidence: 99%