Mucopolysaccharidosis IIIC (MPS IIIC, or Sanfilippo C syndrome) is a lysosomal storage disorder caused by the inherited deficiency of the lysosomal membrane enzyme acetyl-coenzyme A: alpha -glucosaminide N-acetyltransferase (N-acetyltransferase), which leads to impaired degradation of heparan sulfate. We report the narrowing of the candidate region to a 2.6-cM interval between D8S1051 and D8S1831 and the identification of the transmembrane protein 76 gene (TMEM76), which encodes a 73-kDa protein with predicted multiple transmembrane domains and glycosylation sites, as the gene that causes MPS IIIC when it is mutated. Four nonsense mutations, 3 frameshift mutations due to deletions or a duplication, 6 splice-site mutations, and 14 missense mutations were identified among 30 probands with MPS IIIC. Functional expression of human TMEM76 and the mouse ortholog demonstrates that it is the gene that encodes the lysosomal N-acetyltransferase and suggests that this enzyme belongs to a new structural class of proteins that transport the activated acetyl residues across the cell membrane.

Institute for Inherited Metabolic Disorders Charles University 1st School of Medicine Prague Czech Republic

Zobrazit více v PubMed

BLAST, http://www.ncbi.nlm.nih.gov/blast/ (used to identify ortholog protein sequences)

Entrez Gene, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene (for GeneID 138050)

GenBank, http://www.ncbi.nih.gov/Genbank/ (for accession numbers AK152926.1, AK149883.1, DR000652.1, XM_372038.4, NT_007995.14, XP_539948.2, XP_588978.2, XP_341451.2, and XP_519741.1)

Human Genome Variation Society, http://www.hgvs.org/

Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for MPS IIIA, IIIB, IIIC, and IID)

The R Project for Statistical Computing, http://www.r-project.org/ PubMed

Rome LH, Hill DF, Bame KJ, Crain LR (1983) Utilization of exogenously added acetyl coenzyme A by intact isolated lysosomes. J Biol Chem 258:3006–3011 PubMed

Bame KJ, Rome LH (1985) Acetyl-coenzyme A:α-glucosaminide N-acetyltransferase: evidence for a transmembrane acetylation mechanism. J Biol Chem 260:11293–11299 PubMed

Pohlmann R, Klein U, Fromme HG, von Figura K (1981) Localisation of acetyl-CoA: α-glucosaminide N-acetyltransferase in microsomes and lysosomes of rat liver. Hoppe Seylers Z Physiol Chem 362:1199–1207 PubMed

Hopwood JJ, Freeman C, Clements PR, Stein R, Miller AL (1983) Cellular location of N-acetyltransferase activities toward glucosamine and glucosamine-6-phosphate in cultured human skin fibroblasts. Biochem Int 6:823–830 PubMed

Meikle PJ, Whittle AM, Hopwood JJ (1995) Human acetyl-coenzyme A:α-glucosaminide N-acetyltransferase: kinetic characterization and mechanistic interpretation. Biochem J 308:327–333 PubMed PMC

Kresse H, von Figura K, Bartsocas C (1976) Clinical and biochemical findings in a family with Sanfilippo disease, type C. Clin Genet 10:364

Bartsocas C, Grobe H, van de Kamp JJ, von Figura K, Kresse H, Klein U, Giesberts MA (1979) Sanfilippo type C disease: clinical findings in four patients with a new variant of mucopolysaccharidosis III. Eur J Pediatr 130:251–25810.1007/BF00441361 PubMed DOI

Klein U, Kresse H, von Figura K (1978) Sanfilippo syndrome type C: deficiency of acetyl-CoA:α-glucosaminide N-acetyltransferase in skin fibroblasts. Proc Natl Acad Sci USA 75:5185–518910.1073/pnas.75.10.5185 PubMed DOI PMC

Sanfilippo SJ, Podosin R, Langer LO Jr, Good RA (1963) Mental retardation associated with acid mucopolysacchariduria (heparitin sulfate type). J Pediatr 63:837–83810.1016/S0022-3476(63)80279-6 DOI

Klein U, van de Kamp JJP, von Figura K, Pohlmann R (1981) Sanfilippo syndrome type C: assay for acetyl-CoA:α-glucosaminide N-acetyltransferase in leukocytes for detection of homozygous and heterozygous individuals. Clin Genet 20:55–59 PubMed

Meikle PJ, Hopwood JJ, Clague AE, Carey WF (1999) Prevalence of lysosomal storage disorders. JAMA 281:249–25410.1001/jama.281.3.249 PubMed DOI

Pinto R, Caseiro C, Lemos M, Lopes L, Fontes A, Ribeiro H, Pinto E, Silva E, Rocha S, Marcao A, Ribeiro I, Lacerda L, Ribeiro G, Amaral O, Sa Miranda MC (2004) Prevalence of lysosomal storage diseases in Portugal. Eur J Hum Genet 12:87–9210.1038/sj.ejhg.5201044 PubMed DOI

Poorthuis BJ, Wevers RA, Kleijer WJ, Groener JE, de Jong JG, van Weely S, Niezen-Koning KE, van Diggelen OP (1999) The frequency of lysosomal storage diseases in The Netherlands. Hum Genet 105:151–156 PubMed

Zaremba J, Kleijer WJ, Juijmans JG, Poorthuis B, Fidzianska E, Glogowska I (1992) Chromosomes 14 and 21 as possible candidates for mapping the gene for Sanfilippo disease type IIIC. J Med Genet 29:514 PubMed PMC

Ausseil J, Loredo-Osti JC, Verner A, Darmond-Zwaig C, Maire I, Poorthuis B, van Diggelen OP, Hudson TJ, Fujiwara TM, Morgan K, Pshezhetsky AV (2004) Localization of a gene for mucopolysaccharidosis IIIC to chromosome region 8p11-8q11. J Med Genet 41:941–94510.1136/jmg.2004.021501 PubMed DOI PMC

Seyrantepe V, Tihy F, Pshezhetsky AV (2006) The microcell-mediated transfer of human chromosome 8 restores the deficient N-acetylytransferase activity in skin fibroblasts of mucopolysaccharidosis type IIIC patients. Hum Genet 120:293–29610.1007/s00439-006-0211-4 PubMed DOI

Kong X, Murphy K, Raj T, He C, White PS, Matise TC (2004) A combined linkage-physical map of the human genome. Am J Hum Genet 75:1143–1148 PubMed PMC

Mira MT, Alcais A, Nguyen VT, Moraes MO, Di Flumeri C, Vu HT, Mai CP, Nguyen TH, Nguyen NB, Pham XK, Sarno EN, Alter A, Montpetit A, Moraes ME, Moraes JR, Dore C, Gallant CJ, Lepage P, Verner A, Van De Vosse E, Hudson TJ, Abel L, Schurr E (2004) Susceptibility to leprosy is associated with PARK2 and PACRG. Nature 427:636–64010.1038/nature02326 PubMed DOI

Sobel E, Lange K (1996) Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker sharing statistics. Am J Hum Genet 58:1323–1337 PubMed PMC

Sobel E, Papp JC, Lange K (2002) Detection and integration of genotyping errors in statistical genetics. Am J Hum Genet 70:496–508 PubMed PMC

Hodanova K, Majewski J, Kublova M, Vyletal P, Kalbacova M, Stiburkova B, Hulkova H, Chagnon YC, Lanouette CM, Marinaki A, Fryns JP, Venkat-Raman G, Kmoch S (2005) Mapping of a new candidate locus for uromodulin-associated kidney disease (UAKD) to chromosome 1q41. Kidney Int 68:1472–148210.1111/j.1523-1755.2005.00560.x PubMed DOI

O’Connell JR, Weeks DE (1998) PedCheck: a program for identifying genotype incompatibilities in linkage analysis. Am J Hum Genet 63:259–266 PubMed PMC

Voznyi YV, Karpova EA, Dudukina TV, Tsvetkova IV, Boer AM, Janse HC, van Diggelen OP (1993). A fluorimetric enzyme assay for the diagnosis of Sanfilippo disease C (MPS III C). J Inher Metab Dis 16:465–47210.1007/BF00710299 PubMed DOI

Gudbjartsson DF, Jonasson K, Frigge M, Kong A (2000) Allegro, a new computer program for multipoint linkage analysis. Nat Genet 25:12–1310.1038/75514 PubMed DOI

Smyth GK (2005) Limma: linear models for microarray data. In: Gentleman R, Carey V, Dudoit S, Irizarry R, Huber W (eds) Bioinformatics and computational biology solutions using R and Bioconductor. Springer, New York, pp 397–420

Smyth GK (2004) Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3:article 3 PubMed

Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 57:289–300

Kmoch S, Hartmannova H, Stiburkova B, Krijt J, Zikanova M, Sebesta I (2000) Human adenylosuccinate lyase (ADSL), cloning and characterization of full-length cDNA and its isoform, gene structure and molecular basis for ADSL deficiency in six patients. Hum Mol Genet 9:1501–151310.1093/hmg/9.10.1501 PubMed DOI

Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–25410.1016/0003-2697(76)90527-3 PubMed DOI

Hinrichs AS, Karolchik D, Baertsch R, Barber GP, Bejerano G, Clawson H, Diekhans M, et al (2006) The UCSC Genome Browser Database: update 2006. Nucleic Acids Res 34:D590–D59810.1093/nar/gkj144 PubMed DOI PMC

Ausseil J, Landry K, Seyrantepe V, Trudel S, Mazur A, Lapointe F, Pshezhetsky AV (2006) An acetylated 120-kDa lysosomal transmembrane protein is absent from mucopolysaccharidosis IIIC fibroblasts: a candidate molecule for MPS IIIC. Mol Genet Metab 87:22–3110.1016/j.ymgme.2005.09.021 PubMed DOI

Kahsay RY, Gao G, Liao L (2005) An improved hidden Markov model for transmembrane protein detection and topology prediction and its applications to complete genomes. Bioinformatics 21:1853–185810.1093/bioinformatics/bti303 PubMed DOI

Jensen LJ, Gupta R, Blom N, Devos D, Tamames J, Kesmir C, Nielsen H, Staerfeldt HH, Rapacki K, Workman C, Andersen CA, Knudsen S, Krogh A, Valencia A, Brunak S (2002) Prediction of human protein function from post-translational modifications and localization features. J Mol Biol 319:1257–126510.1016/S0022-2836(02)00379-0 PubMed DOI

Blom N, Sicheritz-Ponten T, Gupta R, Gammeltoft S, Brunak S (2004) Prediction of post-translational glycosylation and phosphorylation of proteins from the amino acid sequence. Proteomics 4:1633–164910.1002/pmic.200300771 PubMed DOI

Bonifacino JS, Traub LM (2003) Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annu Rev Biochem 72:395–44710.1146/annurev.biochem.72.121801.161800 PubMed DOI

Bame KJ, Rome LH (1986a) Acetyl-coenzyme A:α-glucosaminide N-acetyltransferase: evidence for an active site histidine residue. J Biol Chem 261:10127–10132 PubMed

Bame KJ, Rome LH (1986b) Genetic evidence for transmembrane acetylation by lysosomes. Science 233:1087–1089 PubMed

Meikle PJ, Whittle AM, Hopwood JJ (1995) Human acetyl-coenzyme A:α-glucosaminide N-acetyltransferase: kinetic characterization and mechanistic interpretation. Biochem J 308:327–333 PubMed PMC

Development of a human mitochondrial oligonucleotide microarray (h-MitoArray) and gene expression analysis of fibroblast cell lines from 13 patients with isolated F1Fo ATP synthase deficiency

Zobrazit více v PubMed

GENBANK
AK149883, DR000652

OMIM
252930

RefSeq
NT_007995, XM_372038, XP_341451, XP_519741, XP_539948, XP_588978