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; Löscher, W; Vondráček, P; Seemann, P; De Jonghe, P; Van Dijck, P; Jordanova, A; Hornemann, T; Timmerman, V (2010). Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. American Journal of Human Genetics, 87(4):513-522.
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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.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Institute of Clinical Chemistry
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
04 Faculty of Medicine > Center for Integrative Human Physiology
|Dewey Decimal Classification:||570 Life sciences; biology
610 Medicine & health
|Deposited On:||16 Feb 2011 13:20|
|Last Modified:||27 Nov 2013 19:50|
|Free access at:||PubMed ID. An embargo period may apply.|
|Related URLs:||http://www.cell.com/AJHG/abstract/S0002-9297%2810%2900478-7 (Publisher)|
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