Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation.
Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation.
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DOI：
10.1093/brain/awp198
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发表时间：
2009-10
期刊：
影响因子：
--
通讯作者：
Timmerman V
中科院分区：
文献类型：
--
作者：
Rotthier A;Baets J;De Vriendt E;Jacobs A;Auer-Grumbach M;Lévy N;Bonello-Palot N;Kilic SS;Weis J;Nascimento A;Swinkels M;Kruyt MC;Jordanova A;De Jonghe P;Timmerman V
遗传性感觉和自主神经病变（HSAN）是一种以轴突萎缩和变性为特征的临床和遗传异质性疾病，专门或主要影响感觉和自主神经元。到目前为止，已经在7个基因中发现了疾病相关突变：2个常染色体显性基因（SPTLC1和RAB7）和5个常染色体隐性基因（WNK1/HSN2、NTRK1、NGFB、CCT5和IKBKAP）。我们对100名被诊断为HSAN的家族性和孤立患者的队列进行了6个基因编码序列的系统突变筛选。此外，我们还筛选了编码神经生长因子受体的功能性候选基因NGFR （p75/NTR）。我们在19例患者中发现了SPTLC1、RAB7、WNK1/HSN2和NTRK1的致病突变，其中3个突变以前没有报道过。与NTRK1和WNK1/HSN2突变相关的表型通常分别包括先天性对疼痛和无汗不敏感，以及早发性溃疡致残性感觉神经病变。RAB7突变仅在Charcot-Marie-Tooth型2B （CMT2B）表型患者中发现，这是一种轴突感觉-运动神经病变，伴有明显的溃疡毁损。在SPTLC1中，我们检测到一种新的突变（S331F），对应于以前未知的严重和早发性HSAN表型。NGFB、CCT5和NGFR未见突变。在研究的患者组中，有19%的患者发现了总体疾病相关突变，这表明还有其他基因与HSAN相关。我们的基因型-表型相关性研究拓宽了HSAN的频谱，并为分子和临床诊断提供了额外的见解。
Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations have been identified in seven genes: two genes for autosomal dominant (SPTLC1 and RAB7) and five genes for autosomal recessive forms of HSAN (WNK1/HSN2, NTRK1, NGFB, CCT5 and IKBKAP). We performed a systematic mutation screening of the coding sequences of six of these genes on a cohort of 100 familial and isolated patients diagnosed with HSAN. In addition, we screened the functional candidate gene NGFR (p75/NTR) encoding the nerve growth factor receptor. We identified disease-causing mutations in SPTLC1, RAB7, WNK1/HSN2 and NTRK1 in 19 patients, of which three mutations have not previously been reported. The phenotypes associated with mutations in NTRK1 and WNK1/HSN2 typically consisted of congenital insensitivity to pain and anhidrosis, and early-onset ulcero-mutilating sensory neuropathy, respectively. RAB7 mutations were only found in patients with a Charcot-Marie-Tooth type 2B (CMT2B) phenotype, an axonal sensory-motor neuropathy with pronounced ulcero-mutilations. In SPTLC1, we detected a novel mutation (S331F) corresponding to a previously unknown severe and early-onset HSAN phenotype. No mutations were found in NGFB, CCT5 and NGFR. Overall disease-associated mutations were found in 19% of the studied patient group, suggesting that additional genes are associated with HSAN. Our genotype–phenotype correlation study broadens the spectrum of HSAN and provides additional insights for molecular and clinical diagnosis.
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