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Human genetic disorders of sphingolipid biosynthesis

  • Complex Lipids
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Monogenic defects of sphingolipid biosynthesis have been recently identified in human patients. These enzyme deficiencies affect the synthesis of sphingolipid precursors, ceramides or complex glycosphingolipids. They are transmitted as autosomal recessive or dominant traits, and their resulting phenotypes often replicate the abnormalities seen in murine models deficient for the corresponding enzymes. In quite good agreement with the known critical roles of sphingolipids in cells from the nervous system and the epidermis, these genetic defects clinically manifest as neurological disorders, including paraplegia, epilepsy or peripheral neuropathies, or present with ichthyosis. The present review summarizes the genetic alterations, biochemical changes and clinical symptoms of this new group of inherited metabolic disorders. Hypotheses regarding the molecular pathophysiology and potential treatments of these diseases are also discussed.

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Abbreviations

ARCI:

Autosomal recessive congenital ichthyosis

deoxyCer:

1-deoxy-ceramide

deoxySa:

1-deoxy-sphinganine

deoxymetSa:

1-deoxymethyl-sphinganine

deoxySL:

1-deoxy-sphingolipid

HSAN:

Hereditary sensory and autonomic neuropathy

MRI:

Magnetic resonance imaging

S1P:

Sphingosine 1-phosphate

SL:

Sphingolipid

SPT:

Serine-palmitoyltransferase

References

  • Aleman TS, Soumittra N, Cideciyan AV et al (2009) CERKL mutations cause an autosomal recessive cone-rod dystrophy with inner retinopathy. Invest Ophthalmol Vis Sci 50(12):5944–5954

    Article  PubMed  Google Scholar 

  • Ali M, Ramprasad VL, Soumittra N et al (2008) A missense mutation in the nuclear localization signal sequence of CERKL (p. R106S) causes autosomal recessive retinal degeneration. Mol Vis 14:1960–1964

    CAS  PubMed Central  PubMed  Google Scholar 

  • Auer-Grumbach M, Bode H, Pieber TR et al (2013) Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a distinct syndromic phenotype. Eur J Med Genet 56(5):266–269

    Article  PubMed Central  PubMed  Google Scholar 

  • Auslender N, Sharon D, Abbasi AH, Garzozi HJ, Banin E, Ben-Yosef T (2007) A common founder mutation of CERKL underlies autosomal recessive retinal degeneration with early macular involvement among Yemenite Jews. Invest Ophthalmol Vis Sci 48(12):5431–5438

    Article  PubMed  Google Scholar 

  • Avila-Fernandez A, Riveiro-Alvarez R, Vallespin E et al (2008) CERKL mutations and associated phenotypes in seven Spanish families with autosomal recessive retinitis pigmentosa. Invest Ophthalmol Vis Sci 49(6):2709–2713

    Article  PubMed  Google Scholar 

  • Bayes M, Goldaracena B, Martinez-Mir A et al (1998) A new autosomal recessive retinitis pigmentosa locus maps on chromosome 2q31-q33. J Med Genet 35(2):141–145

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bejaoui K, Uchida Y, Yasuda S et al (2002) Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis. J Clin Invest 110(9):1301–1308

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bejaoui K, Wu C, Scheffler MD et al (2001) SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat Genet 27(3):261–262

    Article  CAS  PubMed  Google Scholar 

  • Ben-David O, Pewzner-Jung Y, Brenner O et al (2011) Encephalopathy caused by ablation of very long acyl chain ceramide synthesis may be largely due to reduced galactosylceramide levels. J Biol Chem 286(34):30022–30033

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Boccuto L, Aoki K, Flanagan-Steet H et al (2013) A mutation in a ganglioside biosynthetic enzyme, ST3GAL5, results in salt & pepper syndrome, a neurocutaneous disorder with altered glycolipid and glycoprotein glycosylation. Hum Mol Genet 23(2):418–433

    Article  PubMed  CAS  Google Scholar 

  • Boukhris A, Schule R, Loureiro JL et al (2013) Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia. Am J Hum Genet 93(1):118–123

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Brown KE, Anderson SM, Young NS (1993) Erythrocyte P antigen: cellular receptor for B19 parvovirus. Science 262(5130):114–117

    Article  CAS  PubMed  Google Scholar 

  • Cao L, Huang XJ, Chen CJ, Chen SD (2013) A rare family with Hereditary Spastic Paraplegia Type 35 due to novel FA2H mutations: a case report with literature review. J Neurol Sci 329(1–2):1–5

    Article  CAS  PubMed  Google Scholar 

  • Chiavegatto S, Sun J, Nelson RJ, Schnaar RL (2000) A functional role for complex gangliosides: motor deficits in GM2/GD2 synthase knockout mice. Exp Neurol 166(2):227–234

    Article  CAS  PubMed  Google Scholar 

  • Citterio A, Arnoldi A, Panzeri E et al (2014) Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis. J Neurol 261(2):373–381

    Article  CAS  PubMed  Google Scholar 

  • Cox TM, Cachon-Gonzalez MB (2012) The cellular pathology of lysosomal diseases. J Pathol 226(2):241–254

    Article  CAS  PubMed  Google Scholar 

  • Cuadros R, Montejo de Garcini E, Wandosell F, Faircloth G, Fernandez-Sousa JM, Avila J (2000) The marine compound spisulosine, an inhibitor of cell proliferation, promotes the disassembly of actin stress fibers. Cancer Lett 152(1):23–29

    Article  CAS  PubMed  Google Scholar 

  • Davidson G, Murphy S, Polke J et al (2012) Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. J Neurol 259(8):1673–1685

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Dawkins JL, Hulme DJ, Brahmbhatt SB, Auer-Grumbach M, Nicholson GA (2001) Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat Genet 27(3):309–312

    Article  CAS  PubMed  Google Scholar 

  • Dick KJ, Eckhardt M, Paisan-Ruiz C et al (2010) Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35). Hum Mutat 31(4):E1251–1260

    Article  CAS  PubMed  Google Scholar 

  • Donkervoort S, Dastgir J, Hu Y et al (2014) Phenotypic variability of a likely FA2H founder mutation in a family with complicated hereditary spastic paraplegia. Clin Genet 85(4):393–395

    Article  CAS  PubMed  Google Scholar 

  • Dyck PJ (1993) Neuronal atrophy and degeneration predominantly affecting peripheral sensory and autonomic neurons. In P J Dyck, K P Thomas, J W Griffin, P A Low, & J F Poduslo (Eds), Peripheral Neuropathy (3rd Editio, pp 1065–1093) Saunders Philladelphia

  • Eckl KM, Tidhar R, Thiele H et al (2013) Impaired epidermal ceramide synthesis causes autosomal recessive congenital ichthyosis and reveals the importance of ceramide acyl chain length. J Invest Dermatol 133(9):2202–2211

    Article  CAS  PubMed  Google Scholar 

  • Edvardson S, Hama H, Shaag A et al (2008) Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. Am J Hum Genet 83(5):643–648

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Farukhi F, Dakkouri C, Wang H, Wiztnitzer M, Traboulsi EI (2006) Etiology of vision loss in ganglioside GM3 synthase deficiency. Ophthalmic Genet 27(3):89–91

    Article  CAS  PubMed  Google Scholar 

  • Fishman PH, Max SR, Tallman JF, Brady RO, Maclaren NK, Cornblath M (1975) Deficient Ganglioside Biosynthesis: a novel human sphingolipidosis. Science 187(4171):68–70

    Article  CAS  PubMed  Google Scholar 

  • Fragaki K, Ait-El-Mkadem S, Chaussenot A et al (2013) Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency. Eur J Hum Genet 21(5):528–534

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Furukawa K, Iwamura K, Uchikawa M et al (2000) Molecular basis for the p phenotype. Identification of distinct and multiple mutations in the alpha 1,4-galactosyltransferase gene in Swedish and Japanese individuals. J Biol Chem 275(48):37752–37756

    Article  CAS  PubMed  Google Scholar 

  • Futerman AH, van Meer G (2004) The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol 5(7):554–565

    Article  CAS  PubMed  Google Scholar 

  • Garanto A, Mandal NA, Egido-Gabas M et al (2013) Specific sphingolipid content decrease in Cerkl knockdown mouse retinas. Exp Eye Res 110:96–106

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Garanto A, Vicente-Tejedor J, Riera M et al (2012) Targeted knockdown of Cerkl, a retinal dystrophy gene, causes mild affectation of the retinal ganglion cell layer. Biochim Biophys Acta 1822(8):1258–1269

    Article  CAS  PubMed  Google Scholar 

  • Garofalo K, Penno A, Schmidt BP et al (2011) Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. J Clin Invest 121(12):4735–4745

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Garone C, Pippucci T, Cordelli DM et al (2011) FA2H-related disorders: a novel c.270 + 3A > T splice-site mutation leads to a complex neurodegenerative phenotype. Dev Med Child Neurol 53(10):958–961

    Article  PubMed  Google Scholar 

  • Graf C, Niwa S, Muller M, Kinzel B, Bornancin F (2008) Wild-type levels of ceramide and ceramide-1-phosphate in the retina of ceramide kinase-like-deficient mice. Biochem Biophys Res Commun 373(1):159–163

    Article  CAS  PubMed  Google Scholar 

  • Hama H (2010) Fatty acid 2-Hydroxylation in mammalian sphingolipid biology. Biochim Biophys Acta 1801(4):405–414

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hammer MB, Eleuch-Fayache G, Schottlaender LV et al (2013) Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. Am J Hum Genet 92(2):245–251

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hanada K (2003) Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism. Biochim Biophys Acta 1632(1–3):16–30

    Article  CAS  PubMed  Google Scholar 

  • Harlalka GV, Lehman A, Chioza B et al (2013) Mutations in B4GALNT1 (GM2 synthase) underlie a new disorder of ganglioside biosynthesis. Brain 136(Pt 12):3618–3624

    Article  PubMed Central  PubMed  Google Scholar 

  • Harris PA, Roman GK, Moulds JJ, Bird GW, Shah NG (1982) An inherited RBC characteristic, NOR, resulting in erythrocyte polyagglutination. Vox Sang 42(3):134–140

    Article  CAS  PubMed  Google Scholar 

  • Hellberg A, Poole J, Olsson ML (2002) Molecular basis of the globoside-deficient P (k) blood group phenotype. Identification of four inactivating mutations in the UDP-N-acetylgalactosamine: globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase gene. J Biol Chem 277(33):29455–29459

    Article  CAS  PubMed  Google Scholar 

  • Hellberg A, Ringressi A, Yahalom V, Safwenberg J, Reid ME, Olsson ML (2004) Genetic heterogeneity at the glycosyltransferase loci underlying the GLOB blood group system and collection. Br J Haematol 125(4):528–536

    Article  CAS  PubMed  Google Scholar 

  • Hellberg A, Schmidt-Melbye AC, Reid ME, Olsson ML (2008) Expression of a novel missense mutation found in the A4GALT gene of Amish individuals with the p phenotype. Transfusion 48(3):479–487

    Article  CAS  PubMed  Google Scholar 

  • Hellberg A, Steffensen R, Yahalom V et al (2003) Additional molecular bases of the clinically important p blood group phenotype. Transfusion 43(7):899–907

    Article  CAS  PubMed  Google Scholar 

  • Huehne K, Zweier C, Raab K et al (2008) Novel missense, insertion and deletion mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with congenital insensitivity to pain with anhidrosis. Neuromuscul Disord 18(2):159–166

    Article  PubMed  Google Scholar 

  • Imgrund S, Hartmann D, Farwanah H et al (2009) Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas. J Biol Chem 284(48):33549–33560

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jennemann R, Rabionet M, Gorgas K et al (2012) Loss of ceramide synthase 3 causes lethal skin barrier disruption. Hum Mol Genet 21(3):586–608

    Article  CAS  PubMed  Google Scholar 

  • Kageyama-Yahara N, Riezman H (2006) Transmembrane topology of ceramide synthase in yeast. Biochem J 398(3):585–593

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Keusch JJ, Manzella SM, Nyame KA, Cummings RD, Baenziger JU (2000) Cloning of Gb3 synthase, the key enzyme in globo-series glycosphingolipid synthesis, predicts a family of alpha 1, 4-glycosyltransferases conserved in plants, insects, and mammals. J Biol Chem 275(33):25315–25321

    Article  CAS  PubMed  Google Scholar 

  • Koda Y, Soejima M, Sato H, Maeda Y, Kimura H (2002) Three-base deletion and one-base insertion of the alpha (1,4) galactosyltransferase gene responsible for the P phenotype. Transfusion 42(1):48–51

    Article  CAS  PubMed  Google Scholar 

  • Kojima Y, Fukumoto S, Furukawa K et al (2000) Molecular cloning of globotriaosylceramide/CD77 synthase, a glycosyltransferase that initiates the synthesis of globo series glycosphingolipids. J Biol Chem 275(20):15152–15156

    Article  CAS  PubMed  Google Scholar 

  • Kruer MC, Paisan-Ruiz C, Boddaert N et al (2010) Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann Neurol 68(5):611–618

    Article  CAS  PubMed  Google Scholar 

  • Kusnierz-Alejska G, Duk M, Storry JR et al (1999) NOR polyagglutination and Sta glycophorin in one family: relation of NOR polyagglutination to terminal alpha-galactose residues and abnormal glycolipids. Transfusion 39(1):32–38

    Article  CAS  PubMed  Google Scholar 

  • Laurá M, Eichler F, Hornemann T, et al (2012) Hereditary sensory and autonomic neuropathy type 1: correlation of severity and plasma atypical deoxy-sphyngoid bases. J Neurol Neurosurg Psychiatry 2012 83 (e1)

  • Levy M, Futerman AH (2010) Mammalian ceramide synthases. IUBMB Life 62(5):347–356

    CAS  PubMed Central  PubMed  Google Scholar 

  • Liao X, Luo Y, Zhan Z, et al (2013) SPG35 contributes to the second common subtype of AR-HSP in China: frequency analysis and functional characterization of FA2H gene mutations. Clin Genet

  • Lingwood CA, Law H, Richardson S et al (1987) Glycolipid binding of purified and recombinant Escherichia coli produced verotoxin in vitro. J Biol Chem 262(18):8834–8839

    CAS  PubMed  Google Scholar 

  • Littink KW, Koenekoop RK, van den Born LI et al (2010) Homozygosity mapping in patients with cone-rod dystrophy: novel mutations and clinical characterizations. Invest Ophthalmol Vis Sci 51(11):5943–5951

    Article  PubMed Central  PubMed  Google Scholar 

  • Liu Y, Su Y, Wiznitzer M, Epifano O, Ladisch S (2008) Ganglioside depletion and EGF responses of human GM3 synthase-deficient fibroblasts. Glycobiology 18(8):593–601

    Article  CAS  PubMed  Google Scholar 

  • Liu YC, Zheng L, Liu Y et al (2013) Pedigree investigation and genetic analysis of a case with p blood group. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 30(6):736–738

    CAS  PubMed  Google Scholar 

  • Lund N, Olsson ML, Ramkumar S et al (2009) The human P (k) histo-blood group antigen provides protection against HIV-1 infection. Blood 113(20):4980–4991

    Article  CAS  PubMed  Google Scholar 

  • Martin E, Schule R, Smets K et al (2013) Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. Am J Hum Genet 92(2):238–244

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mizutani Y, Kihara A, Igarashi Y (2006) LASS3 (longevity assurance homologue 3) is a mainly testis-specific (dihydro) ceramide synthase with relatively broad substrate specificity. Biochem J 398(3):531–538

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mosbech M, Olsen A, Neess D, et al (2014) Reduced ceramide synthase 2 activity causes progressive myoclonic epilepsy. Ann Clin Transl Neurol in press

  • Mullen TD, Hannun YA, Obeid LM (2012) Ceramide synthases at the centre of sphingolipid metabolism and biology. Biochem J 441(3):789–802

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Murphy SM, Ernst D, Wei Y et al (2013) Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2. Neurology 80(23):2106–2111

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Niimi K, Nishioka C, Miyamoto T et al (2011) Impairment of neuropsychological behaviors in ganglioside GM3-knockout mice. Biochem Biophys Res Commun 406(4):524–528

    Article  CAS  PubMed  Google Scholar 

  • Nishiguchi KM, Tearle RG, Liu YP et al (2013) Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene. Proc Natl Acad Sci U S A 110(40):16139–16144

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Okuda T, Tokuda N, Numata S et al (2006) Targeted disruption of Gb3/CD77 synthase gene resulted in the complete deletion of globo-series glycosphingolipids and loss of sensitivity to verotoxins. J Biol Chem 281(15):10230–10235

    Article  CAS  PubMed  Google Scholar 

  • Penno A, Reilly MM, Houlden H et al (2010) Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. J Biol Chem 285(15):11178–11187

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pewzner-Jung Y, Ben-Dor S, Futerman AH (2006) When do Lasses (longevity assurance genes) become CerS (ceramide synthases)? Insights into the regulation of ceramide synthesis. J Biol Chem 281(35):25001–25005

    Article  CAS  PubMed  Google Scholar 

  • Pewzner-Jung Y, Brenner O, Braun S et al (2010a) A critical role for ceramide synthase 2 in liver homeostasis: II. insights into molecular changes leading to hepatopathy. J Biol Chem 285(14):10911–10923

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pewzner-Jung Y, Park H, Laviad EL et al (2010b) A critical role for ceramide synthase 2 in liver homeostasis: I. alterations in lipid metabolic pathways. J Biol Chem 285(14):10902–10910

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pierson TM, Simeonov DR, Sincan M et al (2012) Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration. Eur J Hum Genet 20(4):476–479

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Potter KA, Kern MJ, Fullbright G et al (2011) Central nervous system dysfunction in a mouse model of FA2H deficiency. Glia 59(7):1009–1021

    Article  PubMed Central  PubMed  Google Scholar 

  • Radner FP, Marrakchi S, Kirchmeier P et al (2013) Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans. PLoS Genet 9(6):e1003536

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rautenstrauss B, Neitzel B, Muench C, Haas J, Holinski-Feder E (2009) Late onset hereditary sensory neuropathy type 1 (HSN1) caused by a novel p. C133R missense mutation in SPTLC1. Würzburg, Germany. In: 2009 Meeting of the Peripheral Nerve Society July 4–8, 2009 (p 290 of 381)

  • Riera M, Burguera D, Garcia-Fernandez J, Gonzalez-Duarte R (2013) CERKL knockdown causes retinal degeneration in zebrafish. PLoS One 8(5):e64048

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rotthier A, Auer-Grumbach M, Janssens K et al (2010) Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. Am J Hum Genet 87(4):513–522

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rotthier A, Baets J, De Vriendt E et al (2009) Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation. Brain 132(Pt 10):2699–2711

    Article  PubMed Central  PubMed  Google Scholar 

  • Rotthier A, Baets J, Timmerman V, Janssens K (2012) Mechanisms of disease in hereditary sensory and autonomic neuropathies. Nat Rev Neurol 8(2):73–85

    Article  CAS  PubMed  Google Scholar 

  • Rotthier A, Penno A, Rautenstrauss B et al (2011) Characterization of two mutations in the SPTLC1 subunit of serine palmitoyltransferase associated with hereditary sensory and autonomic neuropathy type I. Hum Mutat 32(6):E2211–2225

    Article  CAS  PubMed  Google Scholar 

  • Rupps R, Hukin J, Balicki M, Mercimek-Mahmutoglu S, Rolfs A, Dias C (2013) Novel Mutations in FA2H-Associated Neurodegeneration: An Underrecognized Condition? J Child Neurol 28(11):1500–1504

    Article  PubMed  Google Scholar 

  • Sabourdy F, Kedjouar B, Sorli SC et al (2008) Functions of sphingolipid metabolism in mammals–lessons from genetic defects. Biochim Biophys Acta 1781(4):145–183

    Article  CAS  PubMed  Google Scholar 

  • Sheikh KA, Sun J, Liu Y et al (1999) Mice lacking complex gangliosides develop Wallerian degeneration and myelination defects. Proc Natl Acad Sci U S A 96(13):7532–7537

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Simpson MA, Cross H, Proukakis C et al (2004) Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase. Nat Genet 36(11):1225–1229

    Article  CAS  PubMed  Google Scholar 

  • Steffensen R, Carlier K, Wiels J et al (2000) Cloning and expression of the histo-blood group Pk UDP-galactose: Ga1beta-4G1cbeta1-cer alpha1, 4-galactosyltransferase. Molecular genetic basis of the p phenotype. J Biol Chem 275(22):16723–16729

    Article  CAS  PubMed  Google Scholar 

  • Suchanowska A, Kaczmarek R, Duk M et al (2012) A single point mutation in the gene encoding Gb3/CD77 synthase causes a rare inherited polyagglutination syndrome. J Biol Chem 287(45):38220–38230

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Suh BC, Hong YB, Nakhro K, Nam SH, Chung KW, Choi BO (2013) Early-onset severe hereditary sensory and autonomic neuropathy type 1 with S331F SPTLC1 mutation. Mol Med Rep 9(2):481–486

    PubMed  Google Scholar 

  • Suh BC, Hong YB, Nakhro K, Nam SH, Chung KW, Choi BO (2014) Early-onset severe hereditary sensory and autonomic neuropathy type 1 with S331F SPTLC1 mutation. Mol Med Rep 9(2):481–486

    CAS  PubMed  Google Scholar 

  • Takamiya K, Yamamoto A, Furukawa K et al (1996) Mice with disrupted GM2/GD2 synthase gene lack complex gangliosides but exhibit only subtle defects in their nervous system. Proc Natl Acad Sci U S A 93(20):10662–10667

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tang Z, Wang Z, Wang Z, Ke T, Wang QK, Liu M (2009) Novel compound heterozygous mutations in CERKL cause autosomal recessive retinitis pigmentosa in a nonconsanguineous Chinese family. Arch Ophthalmol 127(8):1077–1078

    Article  PubMed  Google Scholar 

  • Teufel A, Maass T, Galle PR, Malik N (2009) The longevity assurance homologue of yeast lag1 (Lass) gene family (review). Int J Mol Med 23(2):135–140

    CAS  PubMed  Google Scholar 

  • Thuresson B, Westman JS, Olsson ML (2011) Identification of a novel A4GALT exon reveals the genetic basis of the P1/P2 histo-blood groups. Blood 117(2):678–687

    Article  CAS  PubMed  Google Scholar 

  • Tonelli A, D’Angelo MG, Arrigoni F et al (2012) Atypical adult onset complicated spastic paraparesis with thin corpus callosum in two patients carrying a novel FA2H mutation. Eur J Neurol 19(11):e127–129

    Article  CAS  PubMed  Google Scholar 

  • Tuson M, Marfany G, Gonzalez-Duarte R (2004) Mutation of CERKL, a novel human ceramide kinase gene, causes autosomal recessive retinitis pigmentosa (RP26). Am J Hum Genet 74(1):128–138

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Verhoeven K, Coen K, De Vriendt E et al (2004) SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I. Neurology 62(6):1001–1002

    Article  CAS  PubMed  Google Scholar 

  • Vanni N, Fruscione F, Ferlazzo E et al. (2014) Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy. Ann Neurol (in press)

  • Votsi C, Zamba-Papanicolaou E, Middleton LT, Pantzaris M, Christodoulou K (2014) A novel GBA2 gene missense mutation in spastic ataxia. Ann Hum Genet 78(1):13–22

    Article  CAS  PubMed  Google Scholar 

  • Wakil SM, Monies DM, Ramzan K, et al (2013) Novel B4GALNT1 mutations in a complicated form of hereditary spastic paraplegia. Clin Genet

  • Wang H, Bright A, Xin B, Bockoven JR, Paller AS (2013) Cutaneous dyspigmentation in patients with ganglioside GM3 synthase deficiency. Am J Med Genet A 161A(4):875–879

    Article  PubMed  CAS  Google Scholar 

  • Wang YC, Chang CF, Lin HC et al (2011) Functional characterisation of a complex mutation in the alpha (1,4) galactosyltransferase gene in Taiwanese individuals with p phenotype. Transfus Med 21(2):84–89

    Article  PubMed  Google Scholar 

  • Wei L, Ji YL, Luo H et al (2012) Serological and genetic study of a pedigree featuring a rare p phenotype. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 29(6):701–704

    CAS  PubMed  Google Scholar 

  • Westman JS, Hellberg A, Peyrard T, Hustinx H, Thuresson B, Olsson ML (2013) P1/P2 genotyping of known and novel null alleles in the P1PK and GLOB histo-blood group systems. Transfusion 53(11 Suppl 2):2928–2939

    CAS  PubMed  Google Scholar 

  • Wilkinson PA, Simpson MA, Bastaki L et al (2005) A new locus for autosomal recessive complicated hereditary spastic paraplegia (SPG26) maps to chromosome 12p11.1-12q14. J Med Genet 42(1):80–82

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xu YH, Barnes S, Sun Y, Grabowski GA (2010) Multi-system disorders of glycosphingolipid and ganglioside metabolism. J Lipid Res 51(7):1643–1675

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yamashita T, Hashiramoto A, Haluzik M et al (2003) Enhanced insulin sensitivity in mice lacking ganglioside GM3. Proc Natl Acad Sci U S A 100(6):3445–3449

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yan LX, Zhu FM, Xu XG, Hong XZ (2003) One base deletion of the alpha (1,4) galactosyltransferase gene responsible for p phenotype. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 20(6):495–498

    CAS  PubMed  Google Scholar 

  • Yildiz Y, Matern H, Thompson B et al (2006) Mutation of beta-glucosidase 2 causes glycolipid storage disease and impaired male fertility. J Clin Invest 116(11):2985–2994

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yoshikawa M, Go S, Takasaki K et al (2009) Mice lacking ganglioside GM3 synthase exhibit complete hearing loss due to selective degeneration of the organ of Corti. Proc Natl Acad Sci U S A 106(23):9483–9488

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zitomer NC, Mitchell T, Voss KA et al (2009) Ceramide synthase inhibition by fumonisin B1 causes accumulation of 1-deoxysphinganine: a novel category of bioactive 1-deoxysphingoid bases and 1-deoxydihydroceramides biosynthesized by mammalian cell lines and animals. J Biol Chem 284(8):4786–4795

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zoller I, Meixner M, Hartmann D et al (2008) Absence of 2-hydroxylated sphingolipids is compatible with normal neural development but causes late-onset axon and myelin sheath degeneration. J Neurosci 28(39):9741–9754

    Article  PubMed  CAS  Google Scholar 

  • Zuellig RA, Hornemann T, Othman A et al (2014) Deoxysphingolipids, novel biomarkers for type 2 diabetes, are cytotoxic for insulin-producing cells. Diabetes 63(4):1326–1339

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by INSERM, Université Paul Sabatier, ANR (SphingoDR program), RITC, LNCC (Equipe Labellisée 2013), CHU Toulouse, and the Vaincre les Maladies Lysosomales Foundation (for TL’s group), and the Gebert Rüf Foundation, the Center for Integrative Human Physiology (ZIHP, University of Zurich), “radiz” – Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, and the European Commission (LSHM-CT-2006-037631) (for TH’s group).

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Centre de Recherches en Cancérologie de Toulouse (CRCT), Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037, Team n 4, CHU Rangueil, BP, 84225, 31432, Toulouse, France

    Leonardo Astudillo, Frédérique Sabourdy, Nicole Therville, Bruno Ségui, Nathalie Andrieu-Abadie & Thierry Levade

  2. Equipe Labellisée Ligue Nationale Contre le Cancer 2013, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, Toulouse, France

    Leonardo Astudillo, Frédérique Sabourdy, Nicole Therville, Bruno Ségui, Nathalie Andrieu-Abadie & Thierry Levade

  3. Service de Médecine Interne, CHU Purpan, Toulouse, France

    Leonardo Astudillo

  4. Laboratoire de Biochimie Métabolique, Institut Fédératif de Biologie, CHU Purpan, Toulouse, France

    Frédérique Sabourdy & Thierry Levade

  5. Institute for Clinical Chemistry, University Hospital Zurich and Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland

    Heiko Bode & Thorsten Hornemann

Authors
  1. Leonardo Astudillo
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  2. Frédérique Sabourdy
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  3. Nicole Therville
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  4. Heiko Bode
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  5. Bruno Ségui
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  6. Nathalie Andrieu-Abadie
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  7. Thorsten Hornemann
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  8. Thierry Levade
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Corresponding author

Correspondence to Thierry Levade.

Additional information

Communicated by: Jean-Marie Saudubray

A homozygous missense mutation (p.H183Q) in the gene encoding ceramide synthase 1 (CERS1) has just been identified in Algerian siblings affected with myoclonic epilepsy and cognitive decline. This autosomal recessive condition is presumably linked to defective biosynthesis of C18-ceramides (Vanni et al. 2014).

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Astudillo, L., Sabourdy, F., Therville, N. et al. Human genetic disorders of sphingolipid biosynthesis. J Inherit Metab Dis 38, 65–76 (2015). https://doi.org/10.1007/s10545-014-9736-1

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  • DOI: https://doi.org/10.1007/s10545-014-9736-1

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