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A Novel Functional Missense Mutation p.T219A in Type 1 Gaucher's Disease.

ABSTRACT: Gaucher's disease (GD) is an autosomal recessive disorder caused by a deficiency of acid ?-glucosidase (glucocerebrosidase [GBA]) that results in the accumulation of glucocerebroside within macrophages. Many mutations have been reported to be associated with this disorder. This study aimed to discover more mutations and provide data for the genetic pattern of the gene, which will help the development of quick and accurate genetic diagnostic tools for this disease.Genomic DNA was obtained from peripheral blood leukocytes of the patient and Sanger sequencing is used to sequence GBA gene. Sequence alignments of mammalian ?-GBA (GCase) and three-dimensional protein structure prediction of the mutation were made. A construct of this mutant and its compound heterozygous counterpart were used to measure GCase in vitro.GCase is relatively conserved at p.T219A. This novel mutation differs from its wild-type in structure. Moreover, it also causes a reduction in GCase enzyme activity.This novel mutation (c.655A>G, p.T219A) is a pathogenic missense mutation, which contributes to GD.

SUBMITTER: Liu LY

PROVIDER: S-EPMC4852675 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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A Novel Functional Missense Mutation p.T219A in Type 1 Gaucher's Disease.

Liu Lin-Yu LY Liu Fei F Du Si-Chen SC Jiang Sha-Yi SY Wang Hui-Jun HJ Zhang Jin J Wang Wei W Ma Duan D

Chinese medical journal 20160501 9

<h4>Background</h4>Gaucher's disease (GD) is an autosomal recessive disorder caused by a deficiency of acid β-glucosidase (glucocerebrosidase [GBA]) that results in the accumulation of glucocerebroside within macrophages. Many mutations have been reported to be associated with this disorder. This study aimed to discover more mutations and provide data for the genetic pattern of the gene, which will help the development of quick and accurate genetic diagnostic tools for this disease.<h4>Methods</ ...[more]

PMID: 27098793

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Project description:BackgroundChronic neuronopathic Gaucher's disease type 3 (GD3) is relatively frequent in northern Sweden. Besides multiple other neurological symptoms, horizontal gaze palsy or oculomotor apraxia is common in GD3.ObjectiveTo characterize the saccades in patients with Norrbottnian GD3 with respect to their neurological and cognitive status using a computer-based eye-tracking technique.MethodsHorizontal and vertical reflexive saccades as well as antisaccades of nine GD3 patients [4M/5F; 41.1 ± 11.0 years; modified severity scoring tool (mSST): 9.3 ± 5.4; Montreal Cognitive Assessment (MoCA): 24.0 ± 4.2] and age-matched controls were analyzed using EyeBrain T2, a head-mounted binocular eye tracker. Systematic clinical assessment included the mSST, a valid tool for monitoring the neurological progression in GD3 and MoCA.ResultsIn Norrbottnian GD3 patients, gain, peak, and average velocity (107.5°/s ± 41.8 vs. 283.9°/s ± 17.0; p = 0.0009) of horizontal saccades were reduced compared to healthy controls (HCs). Regarding vertical saccades, only the average velocity of downward saccades was decreased (128.6°/s ± 63.4 vs. 244.1°/s ± 50.8; p = 0.004). Vertical and horizontal saccadic latencies were increased (294.3 ms ± 37.0 vs. 236.5 ms ± 22.4; p = 0.005) and the latency of horizontal reflexive saccades was correlated with the mSST score (R2 = 0.80; p = 0.003). The latency of antisaccades showed association to MoCA score (R2 = 0.70; p = 0.009). GD3 patients made more errors in the antisaccade task (41.5 ± 27.6% vs. 5.2 ± 5.8%; p = 0.005), and the error rate tended to correlate with the cognitive function measured in MoCA score (p = 0.06).ConclusionThe mean age of 41 years of our GD3 cohort reflects the increased life expectancy of patients in the Norrbottnian area compared to other GD3 cohorts. Marked impairment of horizontal saccades was evident in all patients, whereas vertical saccades showed distinct impairment of downward velocity. Latency of reflexive saccades was associated with the severity of neurological symptoms. Increased latency and error rate in the antisaccade task were linked to cognitive impairment. The assessment of saccades provides markers for neurological and neuropsychological involvement in Norrbottnian GD3.

Dataset Information

A Novel Functional Missense Mutation p.T219A in Type 1 Gaucher's Disease.

Publications

A Novel Functional Missense Mutation p.T219A in Type 1 Gaucher's Disease.

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