Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 May 11;23(10):5368.
doi: 10.3390/ijms23105368.

Ganglioside GM3 Synthase Deficiency in Mouse Models and Human Patients

Kei-Ichiro Inamori  1 , Jin-Ichi Inokuchi  1   2
Affiliations
Review

Ganglioside GM3 Synthase Deficiency in Mouse Models and Human Patients

Kei-Ichiro Inamori et al. Int J Mol Sci. .

Abstract

Gangliosides (glycosphingolipids containing one or more sialic acids) are highly expressed in neural tissues in vertebrates, and four species (GM1a, GD1a, GD1b, GT1b) are predominant in mammalian brains. GM3 is the precursor of each of these four species and is the major ganglioside in many nonneural tissues. GM3 synthase (GM3S), encoded by ST3GAL5 gene in humans, is a sialyltransferase responsible for synthesis of GM3 from its precursor, lactosylceramide. ST3GAL5 mutations cause an autosomal recessive form of severe infantile-onset neurological disease characterized by progressive microcephaly, intellectual disability, dyskinetic movements, blindness, deafness, intractable seizures, and pigment changes. Some of these clinical features are consistently present in patients with ST3GAL5 mutations, whereas others have variable expression. GM3S knockout (KO) mice have deafness and enhanced insulin sensitivity, but otherwise do not display the above-described neurological defects reported in ST3GAL5 patients. The authors present an overview of physiological functions and pathological aspects of gangliosides based on findings from studies of GM3S KO mice and discuss differential phenotypes of GM3S KO mice versus human GM3S-deficiency patients.

Keywords: GM3 synthase; GM3S deficiency; ST3GAL5; gangliosides; glycosyltransferase.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing financial interests or personal relationships that could influence the findings described in this article.

Figures

Figure 1
Figure 1
Biosynthetic pathway of gangliosides and sulfatide. GlcCerS catalyzes with the addition of glucose to ceramide, and LacCerS subsequently adds galactose to GlcCer to form LacCer. GalCerS catalyzes with the addition of galactose to ceramide to form GalCer, and CST subsequently adds a sulfate group to form sulfatide SM4. Red rectangles indicate phenotypes observed in mouse KO models. Expression of globo-type GSLs (highlighted by blue rectangle) is elevated substantially in fibroblasts of human GM3S-deficiency patients. In contrast, in GM3S KO-mouse brains and fibroblasts, expression of globo-type GSLs is only slightly elevated, but that of o-series gangliosides (GM1b, GD1α, GD1c: highlighted by yellow rectangle) is elevated substantially (see main text).
Figure 2
Figure 2
Sialyl motifs of ST3GAL5 and its variants detected in GM3S-deficiency patients (schematic) (see Section 4). Sialylmotifs L (large), S (small) and VS (very small) are highly conserved in mammalian sialyltransferases. X419RextX38 is a variant in the stop codon at the position 419, changing it to an R (arginine)-codon and adding a new amino acid extension with a new stop codon at position 38. TM, transmembrane domain.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Inokuchi J., Inamori K., Kabayama K., Nagafuku M., Uemura S., Go S., Suzuki A., Ohno I., Kanoh H., Shishido F. Biology of GM3 ganglioside. Prog. Mol. Biol. Transl. Sci. 2018;156:151–195. - PubMed
    1. Sprong H., Kruithof B., Leijendekker R., Slot J.W., van Meer G., van der Sluijs P. UDP-galactose:ceramide galactosyltransferase is a class I integral membrane protein of the endoplasmic reticulum. J. Biol. Chem. 1998;273:25880–25888. doi: 10.1074/jbc.273.40.25880. - DOI - PubMed
    1. Jeckel D., Karrenbauer A., Burger K.N., van Meer G., Wieland F. Glucosylceramide is synthesized at the cytosolic surface of various Golgi subfractions. J. Cell. Biol. 1992;117:259–267. doi: 10.1083/jcb.117.2.259. - DOI - PMC - PubMed
    1. Schnaar R.L. The biology of gangliosides. Adv. Carbohydr. Chem. Biochem. 2019;76:113–148. - PubMed
    1. Groux-Degroote S., Rodriguez-Walker M., Dewald J.H., Daniotti J.L., Delannoy P. Gangliosides in cancer cell signaling. Prog. Mol. Biol. Transl. Sci. 2018;156:197–227. - PubMed

Substances

Supplementary concepts

-