Exclusion of serine palmitoyltransferase long chain base subunit 2 (SPTLC2) as a common cause for hereditary sensory neuropathy

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Abstract

Recently point mutations in the SPTLC1 subunit of serine palmitoyltransferase have been shown to cause the common form of dominant hereditary sensory neuropathy (HSN1). Serine palmitoyltransferase (SPT) is a heterodimeric molecule made up of two subunits, SPTLC1 and SPTLC2. Twelve index patients from families with presumed genetic sensory neuropathies were screened for SPTLC2 mutations. These families comprised six multigenerational families, including two previously reported families not linked to the SPTLC1 locus on chromosome 9 and one multigenerational family with a complicated hereditary sensory neuropathy syndrome with associated palmar plantar keratosis, ataxia and spastic paraplegia. The remaining families included one consanguineous family with presumed recessive HSN with two affected siblings, one case of congenital sensory neuropathy and four sporadic cases with adult onset sensory neuropathy. No mutations in the SPTLC2 gene were found in any family. These results suggest that SPTLC2 mutations are not a common cause for genetic sensory neuropathies.

Introduction

Hereditary sensory neuropathy (HSN) is a distal axonal degeneration of peripheral nerve. HSN has more prominent sensory involvement than is found in the hereditary motor and sensory neuropathies (HMSN) which are also known as Charcot–Marie–Tooth (CMT) neuropathies. Some motor involvement is present in HSN even in the early descriptions of the disease [1]. Sural nerve biopsy shows a chronic axonal degeneration affecting both large and small fibres. The disease has variously been called hereditary sensory and autonomic neuropathy (HSAN), ulcero-mutilating neuropathy and hereditary sensory radicular neuropathy (see review by Thomas [2]).

Dominantly inherited sensory neuropathy (HSN1) is a genetically heterogeneous disorder in which chromosome 9q22 linked families [3] and non-chromosome 9q22 linked families have been described [4]. In addition, one form of hereditary motor and sensory neuropathy linked to chromosome 3q13-q22 [5], designated HMSN type IIB or CMT2B, has frequent foot ulcers and it has been suggested that this disorder could also be classified as a HSN [6].

Recently, the chromosome 9-linked form of HSN1 has been shown to be caused by mutations in the serine palmitoyltransferase long chain base subunit 1 gene (SPTLC1) [7]. The serine palmitoyltransferase enzyme (SPT) consists of two subunits (SPTLC1 and SPTLC2) in which the second subunit, SPTLC2, is located on chromosome 14 (http://www.ncbi.nlm.nih.gov/UniGene/). If the mechanism causing the disease is alteration of enzyme activity or abnormal protein interactions between the two subunits, then the gene encoding the second subunit could be a candidate gene for the other genetic sensory neuropathies with no mutations in SPTLC1.

We have performed molecular studies to screen SPTLC2 for mutations in 12 families with sensory neuropathies with various modes of inheritance. Two families had multigenerational affected individuals with male to male transmission of the disease and therefore have an autosomal dominant disorder. Four other families had no male to male transmission and are compatible with either dominant or X-linked inheritance. In addition, two families had possible recessive modes of inheritance and there were four sporadic cases (which could also be instances of recessive disease). We also investigated a large non-chromosome 3 and 9 Austrian family, CMT-126 [4], for genetic linkage to the SPTLC2 gene on chromosome 14.

Section snippets

Results and discussion

Comparison of the SPTLC2 cDNA sequence (accession no. Y08686) and human genome sequence databases at NCBI (http://www.ncbi.nlm.nih.gov/blast) revealed that the 1686 bp coding region of SPTLC2 is contained in 12 exons and contains an in frame methionine start codon at nucleotide position 49. The exon containing the methionine start codon was designated as exon 1. Exon 12 contains the stop codon at position 1735.

All 12 exons of SPTLC2 were screened for mutations in at least one affected individual

References (8)

  • E.P. Hicks

    Hereditary perforating ulcer of the foot

    Lancet

    (1922)
  • P.K. Thomas

    Hereditary sensory neuropathies

    Brain Pathol

    (1993)
  • G.A. Nicholson et al.

    The gene for hereditary sensory neuropathy type I (HSN-I) maps to chromosome 9q221-q223

    Nat Genet

    (1996)
  • M. Auer-Grumbach et al.

    Ulcero-mutilating neuropathy in an Austrian kinship without linkage to hereditary motor and sensory neuropathy IIB and hereditary sensory neuropathy I loci

    Neurology

    (2000)
There are more references available in the full text version of this article.

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