Incidental Mutation 'R0044:Gbe1'

• ID: 15454
• Institutional Source: Beutler Lab
• Gene Symbol: Gbe1
• Ensembl Gene: ENSMUSG00000022707
• Gene Name: 1,4-alpha-glucan branching enzyme 1
• Synonyms: 2310045H19Rik, D16Ertd536e, 2810426P10Rik
• MMRRC Submission: 038338-MU
• Essential gene?: Essential (E-score: 1.000)
• Stock #: R0044 (G1)
• Status: Validated
• Chromosome: 16
• Chromosomal Location: 70110837-70366604 bp(+) (GRCm39)
• Type of Mutation: nonsense
• DNA Base Change (assembly): T to A at 70358020 bp (GRCm39)
• Zygosity: Heterozygous
• Amino Acid Change: Tyrosine to Stop codon at position 681 (Y681*)
• Ref Sequence: ENSEMBL: ENSMUSP00000131320
• Gene Model: predicted gene model for transcript(s): [ENSMUST00000023393] [ENSMUST00000163832] [ENSMUST00000170464]
• AlphaFold: Q9D6Y9
• Predicted Effect: probably null; Transcript: ENSMUST00000023393; AA Change: Y681*
• SMART Domains: Protein: ENSMUSP00000023393; Gene: ENSMUSG00000022707; AA Change: Y681*

Domain	Start	End	E-Value	Type
low complexity region	2	9	N/A	INTRINSIC
Pfam:CBM_48	75	161	9.4e-17	PFAM
Pfam:Alpha-amylase	218	336	1.1e-17	PFAM
Pfam:Alpha-amylase_C	603	698	1.3e-24	PFAM

• Predicted Effect: probably null; Transcript: ENSMUST00000163832; AA Change: Y681*
• SMART Domains: Protein: ENSMUSP00000132603; Gene: ENSMUSG00000022707; AA Change: Y681*

Domain	Start	End	E-Value	Type
low complexity region	2	9	N/A	INTRINSIC
Pfam:CBM_48	75	161	6e-19	PFAM
Pfam:Alpha-amylase	220	337	5.9e-14	PFAM
Pfam:Alpha-amylase_C	603	698	2.2e-25	PFAM

• Predicted Effect: noncoding transcript; Transcript: ENSMUST00000169432
• Predicted Effect: probably null; Transcript: ENSMUST00000170464; AA Change: Y681*
• SMART Domains: Protein: ENSMUSP00000131320; Gene: ENSMUSG00000022707; AA Change: Y681*

Domain	Start	End	E-Value	Type
low complexity region	2	9	N/A	INTRINSIC
Pfam:CBM_48	75	161	9.4e-17	PFAM
Pfam:Alpha-amylase	218	336	1.1e-17	PFAM
Pfam:Alpha-amylase_C	603	698	1.3e-24	PFAM

• Meta Mutation Damage Score: 0.9712
• Coding Region Coverage:
  • 1x: 79.0%
  • 3x: 68.4%
  • 10x: 42.5%
  • 20x: 22.8%
• Validation Efficiency: 98% (58/59)
• MGI Phenotype: FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene is a glycogen branching enzyme that catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, in reducing the osmotic pressure within cells. Highest level of this enzyme are found in liver and muscle. Mutations in this gene are associated with glycogen storage disease IV (also known as Andersen's disease). [provided by RefSeq, Jul 2008] ; PHENOTYPE: Mice homozygous for an ENU-induced allele exhibit mid-to-late gestation lethality, decreased heart rate, glycogen storage defects, and ventricles that were small, hypertrabeculated, and noncompacted. [provided by MGI curators]
• Allele List at MGI:

  All alleles(4) : Targeted(3) Chemically induced(1)

• Posted On: 2012-12-21
• Science Writer: Anne Murray

Protein Function and Prediction

GBE1, an amylo-(1,4-1,6)-transglycosylase, catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain to yield a branched polymer with increased water solubility and glycogen synthetic activity (1;2). GBE1 deficiency leads to accumulation of abnormal glycogen (1) and absence of activity is lethal in utero or in infancy affecting primarily muscle and liver (2).

Background

Mutations in GBE1 are linked to glycogen storage disease IV [OMIM: # 232500; (3)] and polyglucosan body disease, adult form [OMIM: # 263570; (4)]. Glycogen storage disease type IV is a clinically heterogeneous disorder. The typical 'classic' hepatic presentation is liver disease of childhood, progressing to lethal cirrhosis. The neuromuscular presentation of GSD IV is distinguished by age at onset into 4 groups: perinatal, presenting as fetal akinesia deformation sequence (FADS) and perinatal death; congenital, with hypotonia, neuronal involvement, and death in early infancy; childhood, with myopathy or cardiomyopathy; and adult, with isolated myopathy or adult polyglucosan body disease (5). Adult polyglucosan body disease is a late-onset, slowly progressive disorder affecting the central and peripheral nervous systems. Patients typically present after age 40 years with a variable combination of cognitive impairment, pyramidal tetraparesis, peripheral neuropathy, and neurogenic bladder. Other manifestations include cerebellar dysfunction and extrapyramidal signs (4).

Gbe1^m1Yty/m1Yty; MGI:4868492

C3HeB/FeJ-Gbe1^m1Yty

Mice homozygous for an ENU-induced allele exhibit mid-to-late gestation lethality, decreased heart rate, glycogen storage defects, and ventricles that were small, hypertrabeculated, and noncompacted (1).

Gbe1^{tm1.1Hoa/tm1.1Hoa}; MGI: 5293612

involves: 129S7/SvEvBrd

Homozygous animals exhibit complete perinatal lethality, abnormal glucose homeostasis and extensive vacuolization of the heart (2).

References

  1. Lee, Y. C., Chang, C. J., Bali, D., Chen, Y. T., and Yan, Y. T. (2011) Glycogen-Branching Enzyme Deficiency Leads to Abnormal Cardiac Development: Novel Insights into Glycogen Storage Disease IV. Hum Mol Genet. 20, 455-465.

  2. Akman, H. O., Sheiko, T., Tay, S. K., Finegold, M. J., Dimauro, S., and Craigen, W. J. (2011) Generation of a Novel Mouse Model that Recapitulates Early and Adult Onset Glycogenosis Type IV. Hum Mol Genet. 20, 4430-4439.

  3. Bao, Y., Kishnani, P., Wu, J. Y., and Chen, Y. T. (1996) Hepatic and Neuromuscular Forms of Glycogen Storage Disease Type IV Caused by Mutations in the Same Glycogen-Branching Enzyme Gene. J Clin Invest. 97, 941-948.

  4. Lossos, A., Meiner, Z., Barash, V., Soffer, D., Schlesinger, I., Abramsky, O., Argov, Z., Shpitzen, S., and Meiner, V. (1998) Adult Polyglucosan Body Disease in Ashkenazi Jewish Patients Carrying the Tyr329Ser Mutation in the Glycogen-Branching Enzyme Gene. Ann Neurol. 44, 867-872.

  5. Bruno, C., van Diggelen, O. P., Cassandrini, D., Gimpelev, M., Giuffre, B., Donati, M. A., Introvini, P., Alegria, A., Assereto, S., Morandi, L., Mora, M., Tonoli, E., Mascelli, S., Traverso, M., Pasquini, E., Bado, M., Vilarinho, L., van Noort, G., Mosca, F., DiMauro, S., Zara, F., and Minetti, C. (2004) Clinical and Genetic Heterogeneity of Branching Enzyme Deficiency (Glycogenosis Type IV). Neurology. 63, 1053-1058.