Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders.
Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders.
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DOI：
10.1186/1471-2377-4-20
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发表时间：
2004-11-30
期刊：
影响因子：
2.6
通讯作者：
Markham AF
中科院分区：
文献类型：
--
作者：
Lynex CN;Carr IM;Leek JP;Achuthan R;Mitchell S;Maher ER;Woods CG;Bonthon DT;Markham AF
脑瘫 (CP) 是一组异质性运动和/或姿势神经障碍，估计发病率为千分之一的活产儿。对称性痉挛性脑瘫的非进行性形式已被识别，其显示出孟德尔常染色体隐性遗传模式。我们最近描述了罕见近亲家族中隐性痉挛 CP 基因座到位于 2q24-31.1 的 5 cM 染色体区域的映射。在这里，我们提供了将该基因座细化至 0.5 cM 区域的数据，其两侧是微卫星标记 D2S2345 和 D2S326。最小区域包含候选基因 GAD1，它编码谷氨酸脱羧酶同工型 (GAD67)，参与氨基酸和兴奋性神经递质谷氨酸向抑制性神经递质 γ-氨基丁酸 (GABA) 的转化。在 GAD67 中检测到一种新的氨基酸错义突变，该突变在受影响的个体中与 CP 分离。这一结果很有趣，因为在僵人综合症 (SPS)、癫痫、小脑性共济失调和巴顿病患者中发现了针对 GAD67 的自身抗体以及更广泛研究的由 GAD2 基因编码的 GAD65 同源物。考虑到 SPS 中存在抗 GAD 抗体以及在不同情况下谷氨酸的兴奋性毒性，GAD1 序列的变异可能会影响谷氨酸/GABA 的比例，这可能是这种形式的痉挛性 CP 的基础，进一步的研究似乎值得进一步研究。在突变分析中检测到 GAD1 单核苷酸取代，并出现在提交给 NCBI SNP 数据库和文献的序列中。这不是一个明确的列表，但包括突变分析时描述的列表。 *Maestrini 等人未提供核苷酸位置。 [47]。
Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts. GAD1 single nucleotide substitutions detected on mutation analysis and occurring in sequences submitted to NCBI SNP database and in the literature. This is not a definitive list, but includes those described at the time of the mutational analysis. *Nucleotide positions were not provided by Maestrini et al. [47].
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作者：
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通讯作者：
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作者：
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DOI：
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