Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (CMTX5)
Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (CMTX5)
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DOI：
10.1086/519529
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发表时间：
2007-09-01
影响因子：
9.8
通讯作者：
Kim, Jong-Won
中科院分区：
文献类型：
--
作者：
Kim, Hee-Jin;Sohn, Kwang-Min;Kim, Jong-Won
我们在两个遗传性周围神经病综合征家系中发现了Xq22.3上PRPS1基因保守氨基酸的错义突变，一个是亚洲血统，一个是欧洲血统。该病呈X连锁隐性遗传，男性患者均表现为语前型感音神经性耳聋，继之为门控障碍和视力丧失。该欧洲血统家族于1967年被报道患有Rosenberg-Chutorian综合征，最近发现一个具有相同症状三联体的韩国家庭在染色体Xq21.32-Q24上发现了一个新的疾病基因CMTX5。PRPS1(磷酸核糖焦磷酸合成酶1)是PRPS基因家族的一种异构体，在包括耳蜗组织在内的人体组织中广泛表达。该酶介导了嘌呤代谢和核苷酸生物合成的关键生化步骤。在Rosenberg-Chutorian综合征患者中发现了E43D突变，在患有CMTX5的韩国患者中发现了M115T突变。我们还发现M115T患者的酶活性降低。PRPS1是第一个编码代谢酶的CMT基因，为了解周围神经的特异性代谢提供了新的线索，也提示了PRPS1作为药物靶点通过抗代谢治疗预防和治疗周围神经病的潜力。
We have identified missense mutations at conserved amino acids in the PRPS1 gene on Xq22.3 in two families with a syndromic form of inherited peripheral neuropathy, one of Asian and one of European descent. The disease is inherited in an X-linked recessive manner, and the affected male patients invariably develop sensorineural hearing loss of prelingual type followed by gating disturbance and visual loss. The family of European descent was reported in 1967 as having Rosenberg-Chutorian syndrome, and recently a Korean family with the same symptom triad was identified with a novel disease locus CMTX5 on the chromosome band Xq21.32-q24. PRPS1 (phosphoribosyl pyrophosphate synthetase 1) is an isoform of the PRPS gene family and is ubiquitously expressed in human tissues, including cochlea. The enzyme mediates the biochemical step critical for purine metabolism and nucleotide biosynthesis. The mutations identified were E43D, in patients with Rosenberg-Chutorian syndrome, and M115T, in the Korean patients with CMTX5. We also showed decreased enzyme activity inpatients with M115T. PRPS1 is the first CMT gene that encodes a metabolic enzyme, shedding a new light on the understanding of peripheral nerve-specific metabolism and also suggesting the potential of PRPS1 as a target for drugs in prevention and treatment of peripheral neuropathy by antimetabolite therapy.