Identification and characterization of 15 novel GALC gene mutations causing Krabbe disease

Tappino, Barbara; Biancheri, Roberta; Mort, Matthew; Regis, Stefano; Corsolini, Fabio; Rossi, Andrea; Stroppiano, Marina; Lualdi, Susanna; Fiumara, Agata; Bembi, Bruno; Rocco, Maja Di; Cooper, David Neil; Filocamo, Mirella

doi:10.1002/humu.21367

Cited by 98 publications

(105 citation statements)

References 29 publications

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“…7B), as has been previously documented in blood samples ( Fig. 7A; % GALC activity) (Tappino et al, 2010;Mirella Filocamo, personal communication). However, when GALC activities were measured in lysosomal fractions from the GLD fibroblasts, both later-onset mutations had low (0.31-0.32 nmol/ h/mg) but significantly higher GALC activity than infantile forms (range, 0.04 -0.23 nmol/h/mg), confirming that there is a correlation between GALC activity in the lysosome and the severity of the phenotype.…”

Section: Additional Later-onset Galc Mutations Also Retain Partial Prsupporting

confidence: 85%

“…Although the majority of this study has been performed in transfected cells on exogenously expressed GALC, we did confirm the improved discrimination of infantile-and later-onset GALC levels in lysosomal fractions prepared from patient fibroblasts. In a future study, we will extend this analysis to total cell lysates versus lysosomal fractions in induced pluripotent stem cells and induced pluripotent stem cell-derived oligodendrocytes from GLD patients (Tappino et al, 2010) to confirm the difference between infantile-and later-onset forms, and the effect of cispolymorphisms, on trafficking, lysosomal processing, and GALC activity.…”

Section: Discussionmentioning

confidence: 91%

“…Lysosomal fractions of dermal fibroblasts from later-onset patients have significantly higher GALC activities than those from infantile-onset patients. A, The table shows clinical and molecular information of GLD dermal fibroblasts used in this study, which were from published (Tappino et al, 2010) and unpublished samples (Mirella Filocamo, Telethon Biobank, Italy). K359AfsX3 (lysine 359 substituted by alanine followed by a frame-shift translational termination) is located close to the frequent 30 kb deletion GLD mutation and therefore will generate a truncation similar to the 30 kb deletion.…”

Section: Discussionmentioning

confidence: 99%

“…7B). Unfortunately, homozygous cells having the G286D, T529M, and Y567S mutations were not available, so we obtained the three mutants in compound heterozygosity with a large deletion mutant, such as the 30 kb GALC deletion (⌬) or K359AfsX3 (Tappino et al, 2010). We assumed that GALC produced from the large deletions in the GALC locus would be low due to nonsense-mediated mRNA decay associated with the premature stop codons, or to protein instability.…”

Section: Additional Later-onset Galc Mutations Also Retain Partial Prmentioning

confidence: 99%

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Altered Trafficking and Processing ofGALCMutants Correlates with Globoid Cell Leukodystrophy Severity

2016

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Globoid cell leukodystrophy (GLD, Krabbe disease) is due to autosomal recessive mutations in the lysosomal enzyme galactosylceramidase (GALC). Many GLD patients develop infantile-onset of progressive neurologic deterioration and death by 2 years of age, whereas others have a later-onset, milder disease. Cord blood transplant slows disease progression much more effectively when performed presymptomatically, highlighting the importance of early diagnosis. Current diagnosis is based on reduced GALC activity, DNA sequence, and clinical examination. However, presymptomatic diagnosis is hampered by imperfect genotype-GALC activity-phenotype correlations. In addition, three polymorphisms in the GALC gene are variably associated with disease mutations and have unknown effects on GALC activity and disease outcome. Here, we study mutations that cause infantile or later-onset GLD, and show that GALC activity is significantly lower in infantile versus later-onset mutants when measured in the lysosomal fraction, but not in whole-cell lysates. In parallel, infantile-onset mutant GALCs showed reduced trafficking to lysosomes and processing than later-onset mutant GALCs. Finally, the cis-polymorphisms also affected trafficking to the lysosome and processing of GALC. These differences potentially explain why the activity of different mutations appears similar in whole-cell extracts from lymphocytes, and suggest that measure of GALC activity in lysosomes may better predict the onset and severity of disease for a given GLD genotype.

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Section: Additional Later-onset Galc Mutations Also Retain Partial Prsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Additional Later-onset Galc Mutations Also Retain Partial Prmentioning

confidence: 99%

See 2 more Smart Citations

Altered Trafficking and Processing ofGALCMutants Correlates with Globoid Cell Leukodystrophy Severity

2016

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“…In this way, the lacking data on the presence of these types of mutations could be obtained. Moreover, in order to establish the functional relevance of mutations detected, in silico analysis tools are employed, as MutPred [15].…”

Section: Identification Of Galc Mutation and Prediction Analysismentioning

confidence: 99%

Genetic Test and Gene Therapy for Krabbe Disease: An Update

Graziano

Cardile²

2014

Gene Technology

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Globoid cell leukodystrophy, also known as Krabbe disease, is an inherited metabolic neurodegenerative disease, due to genetic mutation of β-galactocerebrosidase gene. Here we reviewed how the technological advances in gene analysis have enhanced the enrichment of mutation database. Moreover, we focus on the possibility to develop genetic treatments, hoping that the updating of genetic, clinical and biochemical data will improve for an early and efficient diagnosis, until a definitive treatment option will be identified.

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Genotype and phenotype classification of 29 patients affected by Krabbe disease

et al. 2019

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Krabbe disease is a rare neurodegenerative lysosomal storage disorder caused by mutations in the galactocerebrosidase gene, GALC. Krabbe disease usually affects infants, but has also been reported in older children and adults. Different phenotypes are described based on age at onset. The gene encoding the galactocerebrosidase enzyme was cloned and expressed in 1993, and up until today 117 mutations have been described. In a patient population of Northern European origin, a 30‐kb deletion and two missense mutations, c.1586C>T; p.T529M and c.1700A>C; p.Y567S, are expected to account for 50%‐60% of pathogenic alleles. In this study, we present information on genetic variation, enzyme activity, and phenotypes of 29 patients affected by Krabbe disease. Patient data were collected from patient files at the Department of Clinical Genetics, Rigshospitalet. Ten previously unreported mutations were identified, including four missense mutations; c.1142C>T; p.T381I, c.596G>T; p.R199M, c.443G>A; p.G148E, c.1858G>A; p.G620R, two nonsense mutations; c.863G>A; p.W288*, c.1214c>G; p.S405*, one splice site mutation; c.442+1G>A, one insertion; c.293insT and two deletions; c.1003_1004del, c.887delA. For all of the new mutations, we were able to classify them in phenotype groups. Furthermore, we present a combined allele frequency of the three frequent mutations p.T529M, p.Y567S, and the 30‐kb deletion of 62%, and we describe a broadening of the phenotypes associated with the mutations p.T529M and p.Y567S.

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Identification and characterization of 15 novel GALC gene mutations causing Krabbe disease

Cited by 98 publications

References 29 publications

Altered Trafficking and Processing ofGALCMutants Correlates with Globoid Cell Leukodystrophy Severity

Altered Trafficking and Processing ofGALCMutants Correlates with Globoid Cell Leukodystrophy Severity

Genetic Test and Gene Therapy for Krabbe Disease: An Update

Genotype and phenotype classification of 29 patients affected by Krabbe disease

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