Mutations in the SPTLC2 Subunit of Serine Palmitoyltransferase Cause Hereditary Sensory and Autonomic Neuropathy Type I

ROTTHIER, Annelies, Michaela AUER-GRUMBACH, Katrien JANSSENS, Jonathan BAETS, Anke PENNO, Leonardo ALMEIDA-SOUZA, Kim VAN HOOF, An JACOBS, Els DE VRIENDT, Beate SCHLOTTER-WEIGEL, Wolfgang LÖSCHER, Petr VONDRÁČEK, Pavel SEEMAN, Peter DE JONGHE, Patrick VAN DIJCK, Albena JORDANOVA, Thorsten HORNEMANN and Vincent TIMMERMAN. Mutations in the SPTLC2 Subunit of Serine Palmitoyltransferase Cause Hereditary Sensory and Autonomic Neuropathy Type I. The American Journal of Human Genetics. USA: CELL PRESS, 2010, vol. 87, No 4, p. 513–522. ISSN 0002-9297. Available from: https://dx.doi.org/10.1016/j.ajhg.2010.09.010.

Basic information

• Original name: Mutations in the SPTLC2 Subunit of Serine Palmitoyltransferase Cause Hereditary Sensory and Autonomic Neuropathy Type I
• Authors: ROTTHIER, Annelies (56 Belgium), Michaela AUER-GRUMBACH (40 Austria), Katrien JANSSENS (56 Belgium), Jonathan BAETS (56 Belgium), Anke PENNO (756 Switzerland), Leonardo ALMEIDA-SOUZA (56 Belgium), Kim VAN HOOF (56 Belgium), An JACOBS (56 Belgium), Els DE VRIENDT (56 Belgium), Beate SCHLOTTER-WEIGEL (276 Germany), Wolfgang LÖSCHER (40 Austria), Petr VONDRÁČEK (203 Czech Republic, belonging to the institution), Pavel SEEMAN (203 Czech Republic), Peter DE JONGHE (56 Belgium), Patrick VAN DIJCK (56 Belgium), Albena JORDANOVA (56 Belgium), Thorsten HORNEMANN (756 Switzerland) and Vincent TIMMERMAN (56 Belgium, guarantor).
• Edition: The American Journal of Human Genetics, USA, CELL PRESS, 2010, 0002-9297.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: Genetics and molecular biology
• Country of publisher: United States of America
• Confidentiality degree: is not subject to a state or trade secret
• WWW: URL
• Impact factor: Impact factor: 11.680
• RIV identification code: RIV/00216224:14110/10:00052290
• Organization unit: Faculty of Medicine
• Doi: http://dx.doi.org/10.1016/j.ajhg.2010.09.010
• UT WoS: 000283037600007
• Keywords in English: Mutations; SPTLC2; Subunit; Serine; Palmitoyltransferase; Cause Hereditary Sensory; Autonomic Neuropathy Type I
• Tags: International impact

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.