Disease relevance of SPTLC1

• SPTLC1 is mutated in hereditary sensory neuropathy, type 1 [1].
• 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 [2].
• To assess the regulation of de novo sphingolipid metabolism during PDT-induced apoptosis, Jurkat human T lymphoma and Chinese hamster ovary cells were labeled with [14C]serine, a substrate of serine palmitoyltransferase (SPT), the enzyme catalyzing the initial step in the sphingolipid biosynthesis [3].
• HSAN IV is characterized by absence of reaction to noxious stimuli, recurrent episodes of fever, anhidrosis, self-mutilating behavior and often mental retardation [4].
• Our results suggest a potential role for overexpression of SPT in the processes of cell metastasis [5].

High impact information on SPTLC1

• Hereditary sensory neuropathy type 1 (HSN1, MIM 162400; ref. 1) genetically maps to human chromosome 9q22 (refs. 2-4) [1].
• We report here that the gene encoding a subunit of serine palmitoyltransferase is located within the HSN1 locus, expressed in dorsal root ganglia (DRG) and mutated in HSN1 [1].
• We now show that the HSN1 gene maps to an 8-centiMorgan (cM) region flanked by D9S318 and D9S176 on chromosome 9q22.1-q22 [6].
• Although in HSN1 lymphoblasts, the C133Y and C133W mutations do not alter the steady-state levels of LCB1 and LCB2 subunits, they result in reduced SPT activity and sphingolipid synthesis [7].
• Furthermore, the overproduction of either the LCB1C133Y or LCB1C133W subunit inhibits SPT activity in CHO cells despite the presence of wild-type LCB1 [7].

Chemical compound and disease context of SPTLC1

• N-(4-hydroxyphenyl)retinamide elevates ceramide in neuroblastoma cell lines by coordinate activation of serine palmitoyltransferase and ceramide synthase [8].
• Human neuroblastoma cell lines were labeled with the supravital DNA stain Hoechst 33342, seeded into normal bone marrow, incubated with monoclonal antibodies recognizing neuroblastoma cell surface antigens (HSAN 1.2, antibody 459, antibody 390, BA-1, and Leu-7), and then mixed with magnetic microspheres coated with goat anti-mouse immunoglobulin [9].
• Low doses of LPS produced maximal increases in SPT activity, with half-maximal effect seen at approximately 0.3 microg LPS/100 g body weight [10].
• Myriocin is an inhibitor of SPT and suppresses replication of the hepatitis C virus (HCV) replicon [11].

Biological context of SPTLC1

• The sensorimotor neuropathy phenotype caused by the 399T-->G SPTLC1 mutation is the same as that reported by Campbell and Hoffman and, possibly, the same as that originally described by Hicks [12].
• To determine if the families in the present study that have SPTLC1 mutations are related to English families with HSN1 and, possibly, to the family studied by Hicks, we performed haplotype analysis of four Australian families of English extraction, four English families, and one Austrian family [12].
• Some cases of idiopathic sensory neuropathy could be caused by missense mutations of SPTLC1 and RAB7 and not be recognised as familial [13].
• Recently point mutations in the SPTLC1 subunit of serine palmitoyltransferase have been shown to cause the common form of dominant hereditary sensory neuropathy (HSN1) [2].
• There are two known autosomal dominant genes for the hereditary ulcero-mutilating neuropathies: SPTLC1 (hereditary sensory neuropathy type 1) and RAB7 (Charcot-Marie-Tooth disease type 2B) [14].

Anatomical context of SPTLC1

• UVB irradiation up-regulates serine palmitoyltransferase in cultured human keratinocytes [15].
• These observations link enhanced SPT expression to proliferating cells, such as the lung, stomach, intestinal epithelium, and renal proximal tubular epithelium, and to potentially activated cells such as neurons, chromaffin cells, and mucosal macrophages [16].
• SPT2 was localized in both nuclei and cytoplasm of the adrenomedullary chromaffin cells, whereas SPT1 was primarily cytoplasmic [16].
• However, SPT2 expression was more prominent than SPT1 in the colon mucosal macrophages, the adrenomedullary chromaffin cells and endothelium, and in the uterine endothelium [16].
• Here, we show a 44% reduction of SPT activity in transformed lymphocytes from HSN1 patients with mutation T399G in the SPTLC1 gene [17].

Associations of SPTLC1 with chemical compounds

• Serine palmitoyltransferase (SPT) catalyzes the condensation of serine with palmitoyl-CoA, the first, rate-limiting step in de novo sphingolipid biosynthesis [16].
• This result suggests that the activation of serine palmitoyltransferase is the event responsible for increased ceramide generation during de novo synthesis initiated by etoposide [18].
• Serine palmitoyltransferase (SPT), a membrane-bound enzyme of the endoplasmic reticulum, catalyzes the condensation of palmitoyl coenzyme A (CoA) and L-serine to produce 3-ketodihydrosphingosine [19].
• Purification of the serine palmitoyltransferase complex responsible for sphingoid base synthesis by using affinity peptide chromatography techniques [19].
• Competition analysis of the SPT reaction with various serine analogs showed that all of the amino, carboxyl, and hydroxyl groups of L-serine were responsible for the substrate recognition of the enzyme [19].

Physical interactions of SPTLC1

• The endogenous LCB2 protein was co-purified with the tagged LCB1 protein in purification of SPT [19].

Other interactions of SPTLC1

• SPT is considered to be a heterodimer composed of two subunits, SPTLC1 and SPTLC2 [20].
• No known mutations of SPTLC1 or RAB7 were found in cases of idiopathic sensory neuropathy [13].
• This report extends the spectrum of NTRK1 mutations observed in patients diagnosed with HSAN IV [4].
• We hypothesized that HSAN IV represents a natural model for impaired NGF effect on the neuroendocrine system in humans [21].
• SPB-1, a Chinese hamster ovary cell variant defective in serine palmitoyltransferase activity for sphingolipid synthesis, provides a useful system for studying the effects of sphingolipids and/or cholesterol deprivation on cellular functions and membrane properties [22].

Analytical, diagnostic and therapeutic context of SPTLC1

• In CHK, transcripts for both LCB1 (3.0 kb) and LCB2 (2.3 kb) are evident by Northern blot analysis, and UVB exposure (23 mJ/cm2) induces a delayed 1.8 to 3.3-fold increase in LCB2 mRNA levels (P < 0.01) 48 h after treatment versus non-irradiated control cells [15].
• Expression of mutant SPTLC1 in yeast and mammalian cell cultures dominantly inhibits SPT activity [23].
• Moreover in Chinese hamster ovary cells LCB1 protein underwent substantial photodestruction, and SPT activity was profoundly inhibited after treatment [3].
• Furthermore, we found lower plasma norepinephrine (NE) levels in six HSAN IV patients compared with a control group after the thirst test [21].
• In this study we used immunohistochemistry to observe the presence of the two known subunits of serine palmitoyltransferase (SPT) in proliferating cells, in an in vitro model of wound repair, and in human malignant tissue [5].

References