Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation. |
Authors: |
Rotthier, A Baets, J De Vriendt, E Jacobs, A Auer-Grumbach, M Levy, N Bonello-Palot, N Kilic, SS Weis, J Nascimento, A Swinkels, M Kruyt, MC Jordanova, A De Jonghe, P Timmerman, V
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Citation: |
Rotthier A, etal., Brain. 2009 Oct;132(Pt 10):2699-711. Epub 2009 Aug 3. |
RGD ID: |
5684543 |
Pubmed: |
PMID:19651702 (View Abstract at PubMed) |
PMCID: |
PMC2759337 (View Article at PubMed Central) |
DOI: |
DOI:10.1093/brain/awp198 (Journal Full-text) |
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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Genes (Rattus norvegicus) |
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Ntrk1 (neurotrophic receptor tyrosine kinase 1) |
Genes (Mus musculus) |
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Ntrk1 (neurotrophic tyrosine kinase, receptor, type 1) |
Genes (Homo sapiens) |
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NTRK1 (neurotrophic receptor tyrosine kinase 1) |
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