Incidental Mutation 'P0018:Hgsnat'

• ID: 7735
• Institutional Source: Beutler Lab
• Gene Symbol: Hgsnat
• Ensembl Gene: ENSMUSG00000037260
• Gene Name: heparan-alpha-glucosaminide N-acetyltransferase
• Synonyms: 9430010M12Rik, D8Ertd354e, Tmem76
• MMRRC Submission: 038271-MU
• Essential gene?: Non essential (E-score: 0.000)
• Stock #: P0018 (G1)
• Status: Validated
• Chromosome: 8
• Chromosomal Location: 26434481-26466781 bp(-) (GRCm39)
• Type of Mutation: unclassified
• DNA Base Change (assembly): C to T at 26458382 bp (GRCm39)
• Zygosity: Heterozygous
• Ref Sequence: ENSEMBL: ENSMUSP00000147675
• Gene Model: predicted gene model for transcript(s): [ENSMUST00000037609] [ENSMUST00000211550]
• AlphaFold: Q3UDW8
• Predicted Effect: probably benign; Transcript: ENSMUST00000037609
• SMART Domains: Protein: ENSMUSP00000040356; Gene: ENSMUSG00000037260

Domain	Start	End	E-Value	Type
low complexity region	2	23	N/A	INTRINSIC
transmembrane domain	33	55	N/A	INTRINSIC
transmembrane domain	189	211	N/A	INTRINSIC
Pfam:DUF1624	260	434	6.8e-11	PFAM
Pfam:DUF5009	286	389	2.4e-10	PFAM
transmembrane domain	494	516	N/A	INTRINSIC
transmembrane domain	523	545	N/A	INTRINSIC
transmembrane domain	560	582	N/A	INTRINSIC
transmembrane domain	587	609	N/A	INTRINSIC
transmembrane domain	629	648	N/A	INTRINSIC

• Predicted Effect: noncoding transcript; Transcript: ENSMUST00000209420
• Predicted Effect: probably benign; Transcript: ENSMUST00000211550
• Coding Region Coverage:
  • 1x: 83.8%
  • 3x: 77.4%
  • 10x: 57.9%
  • 20x: 38.3%
• Validation Efficiency: 72% (76/106)
• MGI Phenotype: FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a lysosomal acetyltransferase, which is one of several enzymes involved in the lysosomal degradation of heparin sulfate. Mutations in this gene are associated with Sanfilippo syndrome C, one type of the lysosomal storage disease mucopolysaccaridosis III, which results from impaired degradation of heparan sulfate. [provided by RefSeq, Jan 2009] ; PHENOTYPE: Mice homozygous for a knock-out allele exhibit progressive storage pathology in the CNS and peripheral organs, glycosaminoglycan accumulation in brain and most somatic organs, lysosomal distension and dysfunction, astrocytosis, microgliosis, hepatosplenomegaly, behavioral deficits and premature death. [provided by MGI curators]
• Allele List at MGI:

  All alleles(9) : Targeted(3) Gene trapped(6)

• Posted On: 2012-10-29
• Science Writer: Anne Murray

Protein Function and Prediction

Hgsnat is an enzyme that catalyzes acetylation of the terminal glucosamine residues of heparan sulfate prior to its hydrolysis by alpha-N-acetyl glucosaminidase (1;2).

Expression/Localization

Northern blot analysis revealed ubiquitous expression of HGSNAT; highest expression was in leukocytes, heart lung, placenta, and liver, and much lower expression was found in thymus, colon, and brain.  RT-PCR detected HGSNAT expression in normal human skin, fibroblasts, white blood cells, and skeletal muscle (3). The N-acetyltransferase reaction catalyzed by Hgsnat occurs in the lysosome (2).

Background

Mutations in HGSNAT can lead to Mucopolysaccharidosis type IIIC (Sanfilippo C) [OMIM: #252930; (2-5)], a lysosomal storage diseases due to impaired degradation of heparan sulfate. The disorder is characterized by severe central nervous system degeneration, but only mild somatic disease. Onset of clinical features usually occurs between 2 and 6 years; severe neurologic degeneration occurs in most patients between 6 and 10 years of age, and death occurs typically during the second or third decade of life.

References

  1. Klein, U., Kresse, H., and von Figura, K. (1978) Sanfilippo Syndrome Type C: Deficiency of Acetyl-CoA:Alpha-Glucosaminide N-Acetyltransferase in Skin Fibroblasts. Proc Natl Acad Sci U S A. 75, 5185-5189.

  2. Fan, X., Zhang, H., Zhang, S., Bagshaw, R. D., Tropak, M. B., Callahan, J. W., and Mahuran, D. J. (2006) Identification of the Gene Encoding the Enzyme Deficient in Mucopolysaccharidosis IIIC (Sanfilippo Disease Type C). Am J Hum Genet. 79, 738-744.

  3. Hrebicek, M., Mrazova, L., Seyrantepe, V., Durand, S., Roslin, N. M., Noskova, L., Hartmannova, H., Ivanek, R., Cizkova, A., Poupetova, H., Sikora, J., Urinovska, J., Stranecky, V., Zeman, J., Lepage, P., Roquis, D., Verner, A., Ausseil, J., Beesley, C. E., Maire, I., Poorthuis, B. J., van de Kamp, J., van Diggelen, O. P., Wevers, R. A., Hudson, T. J., Fujiwara, T. M., Majewski, J., Morgan, K., Kmoch, S., and Pshezhetsky, A. V. (2006) Mutations in TMEM76* Cause Mucopolysaccharidosis IIIC (Sanfilippo C Syndrome). Am J Hum Genet. 79, 807-819.

  4. Canals, I., Elalaoui, S. C., Pineda, M., Delgadillo, V., Szlago, M., Jaouad, I. C., Sefiani, A., Chabas, A., Coll, M. J., Grinberg, D., and Vilageliu, L. (2010) Molecular Analysis of Sanfilippo Syndrome Type C in Spain: Seven Novel HGSNAT Mutations and Characterization of the Mutant Alleles. Clin Genet. .

  5. Feldhammer, M., Durand, S., Mrazova, L., Boucher, R. M., Laframboise, R., Steinfeld, R., Wraith, J. E., Michelakakis, H., van Diggelen, O. P., Hrebicek, M., Kmoch, S., and Pshezhetsky, A. V. (2009) Sanfilippo Syndrome Type C: Mutation Spectrum in the Heparan Sulfate Acetyl-CoA: Alpha-Glucosaminide N-Acetyltransferase (HGSNAT) Gene. Hum Mutat. 30, 918-925.