Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Rotthier, A; Auer-Grumbach, M; Janssens, K; Baets, J; Penno, A; Almeida-Souza, L; Van Hoof, K; Jacobs, A; De Vriendt, E; Schlotter-Weigel, B; Loscher, W; Vondracek, P; Seeman, P; De Jonghe, P; Van Dijck, P; Jordanova, A; Hornemann, T; Timmerman, V.
Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I.
AMER J HUM GENET. 2010; 87(4): 513-522.
Doi: 10.1016/j.ajhg.2010.09.010
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- Auer-Grumbach Michaela
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- Abstract:
- Hereditary sensory and autonomic neuropathy type I (HSAN-I) is an axonal peripheral neuropathy associated with progressive distal sensory loss and severe ulcerations. Mutations in the first subunit of the enzyme serine palmitoyltransferase (SPT) have been associated with HSAN-I. The SPT enzyme catalyzes the first and rate-limiting step in the de novo sphingolipid synthesis pathway. However, different studies suggest the implication of other genes in the pathology of HSAN-I. Therefore, we screened the two other known subunits of SPT, SPTLC2 and SPTLC3, in a cohort of 78 HSAN patients. No mutations were found in SPTLC3, but we identified three heterozygous missense mutations in the SPTLC2 subunit of SPT in four families presenting with a typical HSAN-I phenotype. We demonstrate that these mutations result in a partial to complete loss of SPT activity in vitro and in vivo. Moreover, they cause the accumulation of the atypical and neurotoxic sphingoid metabolite 1-deoxy-sphinganine. Our findings extend the genetic heterogeneity in HSAN-I and enlarge the group of HSAN neuropathies associated with SPT defects. We further show that HSAN-I is consistently associated with an increased formation of the neurotoxic 1-deoxysphinganine, suggesting a common pathomechanism for HSAN-I.
- Find related publications in this database (using NLM MeSH Indexing)
- Base Sequence -
- Cell Line -
- Cloning, Molecular -
- Cohort Studies -
- DNA Mutational Analysis -
- DNA Primers - genetics
- Genetic Complementation Test -
- Hereditary Sensory and Autonomic Neuropathies - genetics
- Humans -
- Microsatellite Repeats - genetics
- Molecular Sequence Data -
- Mutation, Missense - genetics
- Serine C-Palmitoyltransferase - genetics Serine C-Palmitoyltransferase - metabolism