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. 2009 Oct;132(Pt 10):2699-711.
doi: 10.1093/brain/awp198. Epub 2009 Aug 3.

Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation

Annelies Rotthier  1 , Jonathan Baets, Els De Vriendt, An Jacobs, Michaela Auer-Grumbach, Nicolas Lévy, Nathalie Bonello-Palot, Sara Sebnem Kilic, Joachim Weis, Andrés Nascimento, Marielle Swinkels, Moyo C Kruyt, Albena Jordanova, Peter De Jonghe, Vincent Timmerman
Affiliations

Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation

Annelies Rotthier et al. Brain. 2009 Oct.

Abstract

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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Figures

Figure 1
Figure 1
Segregation of p.Ser331Phe and p.Ala352Val missense mutations in SPTLC1 (A and B) and segregation and cDNA analysis of the p.Arg565Gln missense mutation in NTRK1 (C and D). Segregation analysis of the p.Ser331Phe missense mutation in SPTLC1 reveals that this mutation occurred de novo (A). Panel B shows the sequence trace file of the p.Ala352Val missense mutation found in SPTLC1 in an isolated Patient CMT-186.05. Segregation of the p.Arg565Gln mutation in NTRK1 is shown in panel C. Two CIPA patients in family CMT-841 (CMT-841.01 and CMT-841.02) had a homozygous Arg565Gln mutation in NTRK1. The healthy siblings of these patients had either the wild-type allele (CMT-841.03 and CMT-841.07) or carried the Arg565Gln mutation in the heterozygous state (CMT-841.04, CMT-841.05 and CMT-841.06). The parents of the patients were first cousins. The mutated nucleotide (c.1697G > A) was the last nucleotide of exon 14, which could affect proper splicing of this exon. cDNA analysis of CMT-841.01 showed the absence of the expected band (528 bp), which was present in the control and confirmed by direct DNA sequencing (D). We could not determine the sequence of the three lower bands present in the patient. square = male, circle = female, black filled symbol = affected, empty symbol = unaffected.
Figure 2
Figure 2
Schematic presentation of protein structures of SPTLC1, RAB7 (Pereira-Leal and Seabra, 2000), WNK1/HSN2 and NTRK1 (Indo, 2001) with mutations identified in this study causing HSAN.
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References

    1. Auer-Grumbach M. Hereditary sensory neuropathies. Drugs Today. 2004;40:385–94. - PubMed
    1. Auer-Grumbach M, De Jonghe P, Verhoeven K, Timmerman V, Wagner K, Hartung HP, et al. Autosomal dominant inherited neuropathies with prominent sensory loss and mutilations: a review. Arch Neurol. 2003;60:329–34. - PubMed
    1. Auer-Grumbach M, Mauko B, Auer-Grumbach P, Pieber TR. Molecular genetics of hereditary sensory neuropathies. Neuromolecular Med. 2006;8:147–58. - PubMed
    1. Axelrod FB, Gold-von Simson G. Hereditary sensory and autonomic neuropathies: types II, III, and IV. Orphanet J Rare Dis. 2007;2:39. - PMC - PubMed
    1. Bejaoui K, Wu C, Scheffler MD, Haan G, Ashby P, Wu L, et al. SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat Genet. 2001;27:261–2. - PubMed

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