Hereditary sensory and autonomic neuropathy II due to novel mutation in the HSN2 gene in Mexican families

Abstract

Mutations in the WNK1/HSN2 (with-no-lysine(K)-1/ hereditary sensory neuropathy 2) gene cause autosomal recessive HSAN2 [1, 2]. HSAN2, an early onset ulceromutilating sensory neuropathy, is clinically characterized by impairment of pain, temperature, and touch sensation. Other characteristics are loss of tendon reflexes, finger ulcers, frequent amputations and virtual absence of myelinated fibers with decreased numbers of unmyelinated fibers in sural nerves [3]. The HSN2, located on 12p13.33, is a nervous systemspecific exon of WNK1 and is referred to as the WNK1/ HSN2 isoform. WNK1/HSN2 encodes a polypeptide of 434 amino acids with a high expression in dorsal root ganglia and sciatic nerves [1, 2]. Apart from HSN2 mutations, a compound heterozygous mutation in exon 6 of WNK1 and in HSN2 [2] and mutations in FAM134B (family with sequence similarity 134, member B) [4] have been identified in HSAN2 demonstrating locus heterogeneity. In the present study, we analyzed two Mexican families with HSAN2 and identified a novel mutation in the WNK1/ HSN2 gene. We evaluated four out of five patients with HSAN2 and 16 healthy members belonging to two families. Family pedigrees are described in Fig. 1 and clinical characteristics are shown in Table 1. Clinical pictures and CT are shown in Fig. 2. Both families came from Chiapas (southeast of Mexico) of distant communities (Ocosingo and San Cristobal de las Casas). Careful examination of heterozygous carriers showed no clinical manifestations. Genomic DNA was extracted from 20 family members and 150 normal controls using standard techniques [5]. The WNK1/HSN2 gene was amplified through PCR [1] and directly sequenced using an ABI Prism Genetic Analyzer (Applied Biosystems, Foster City, CA, USA.) under the supplier’s conditions. All procedures were repeated twice. All members were informed about the characteristics of the study and they agreed to participate. We identified a homozygous mutation in WNK1/HSN2 in affected members of the two HSAN2 families. This mutation is a deletion of eight nucleotides (c. 1219_1226 delTCTCAGCA, NM 213655) that causes a novel stop codon 26 nucleotides after the original stop codon (S407fsX442) (Fig. 1). This mutation was not found in 150 normal controls and healthy members of the family, so we discarded a possible polymorphism. Subjects I1, I2, and III9 from family B were heterozygous with no clinical manifestations. Several mutations in WNK1/HSN2 have been identified among several populations: in Canada E198fs207, S307fsX319, Q315X; in Italy P85fsX98, G. Pacheco-Cuellar L. M. Gonzalez-Huerta J. M. Valdes-Miranda S. A. Cuevas-Covarrubias (&) Servicio de Genetica, Hospital General de Mexico, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Dr. Balmis 148, Col. Doctores, C.P. 06726 Mexico City, DF, Mexico e-mail: sercuevas@yahoo.com; sergioa@servidor.unam.mx