Comprehensive behavioral and biochemical outcomes of novel murine models of GM1-gangliosidosis and Morquio syndrome type B

Michael J. Przybilla, Li Ou, Alexandru Flaviu Tăbăran, Xuntian Jiang, Rohini Sidhu, Pamela J. Kell, Daniel S. Ory, M. Gerard O'Sullivan, Chester B. Whitley

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Deficiencies in the lysosomal hydrolase β-galactosidase (β-gal) lead to two distinct diseases: the skeletal disease Morquio syndrome type B, and the neurodegenerative disease GM1-gangliosidosis. Utilizing CRISPR-Cas9 genome editing, the mouse β-gal encoding gene, Glb1, was targeted to generate both models of β-gal deficiency in a single experiment. For Morquio syndrome type B, the common human missense mutation W273L (position 274 in mice) was introduced into the Glb1 gene (Glb1 W274L ), while for GM1-gangliosidosis, a 20 bp mutation was generated to remove the catalytic nucleophile of β-gal (β-gal −/− ). Glb1 W274L mice showed a significant reduction in β-gal enzyme activity (8.4–13.3% of wildtype), but displayed no marked phenotype after one year. In contrast, β-gal −/− mice were devoid of β-gal enzyme activity (≤1% of wildtype), resulting in ganglioside accumulation and severe cellular vacuolation throughout the central nervous system (CNS). β-gal −/− mice also displayed severe neuromotor and neurocognitive dysfunction, and as the disease progressed, the mice became emaciated and succumbed to the disease by 10 months of age. Overall, in addition to generating a novel murine model that phenotypically resembles GM1-gangliosidosis, the first model of β-galactosidase deficiency with residual enzyme activity has been developed.

Original languageEnglish (US)
Pages (from-to)139-150
Number of pages12
JournalMolecular Genetics and Metabolism
Volume126
Issue number2
DOIs
StatePublished - Feb 2019

Fingerprint

Mucopolysaccharidosis IV
GM1 Gangliosidosis
Enzyme activity
Galactosidases
Clustered Regularly Interspaced Short Palindromic Repeats
Genes
Neurodegenerative diseases
Nucleophiles
Gene encoding
Gangliosides
Neurology
Hydrolases
Enzymes
Missense Mutation
Neurodegenerative Diseases
Central Nervous System
Phenotype
Mutation
Experiments

Keywords

  • Gangliosidosis
  • Lysosomal disease
  • Mouse Model
  • Mucopolysaccharidosis

Cite this

Comprehensive behavioral and biochemical outcomes of novel murine models of GM1-gangliosidosis and Morquio syndrome type B. / Przybilla, Michael J.; Ou, Li; Tăbăran, Alexandru Flaviu; Jiang, Xuntian; Sidhu, Rohini; Kell, Pamela J.; Ory, Daniel S.; O'Sullivan, M. Gerard; Whitley, Chester B.

In: Molecular Genetics and Metabolism, Vol. 126, No. 2, 02.2019, p. 139-150.

Research output: Contribution to journalArticle

Przybilla, Michael J. ; Ou, Li ; Tăbăran, Alexandru Flaviu ; Jiang, Xuntian ; Sidhu, Rohini ; Kell, Pamela J. ; Ory, Daniel S. ; O'Sullivan, M. Gerard ; Whitley, Chester B. / Comprehensive behavioral and biochemical outcomes of novel murine models of GM1-gangliosidosis and Morquio syndrome type B. In: Molecular Genetics and Metabolism. 2019 ; Vol. 126, No. 2. pp. 139-150.
@article{2774d9c40ca7445ea653e0fdaf6aadf5,
title = "Comprehensive behavioral and biochemical outcomes of novel murine models of GM1-gangliosidosis and Morquio syndrome type B",
abstract = "Deficiencies in the lysosomal hydrolase β-galactosidase (β-gal) lead to two distinct diseases: the skeletal disease Morquio syndrome type B, and the neurodegenerative disease GM1-gangliosidosis. Utilizing CRISPR-Cas9 genome editing, the mouse β-gal encoding gene, Glb1, was targeted to generate both models of β-gal deficiency in a single experiment. For Morquio syndrome type B, the common human missense mutation W273L (position 274 in mice) was introduced into the Glb1 gene (Glb1 W274L ), while for GM1-gangliosidosis, a 20 bp mutation was generated to remove the catalytic nucleophile of β-gal (β-gal −/− ). Glb1 W274L mice showed a significant reduction in β-gal enzyme activity (8.4–13.3{\%} of wildtype), but displayed no marked phenotype after one year. In contrast, β-gal −/− mice were devoid of β-gal enzyme activity (≤1{\%} of wildtype), resulting in ganglioside accumulation and severe cellular vacuolation throughout the central nervous system (CNS). β-gal −/− mice also displayed severe neuromotor and neurocognitive dysfunction, and as the disease progressed, the mice became emaciated and succumbed to the disease by 10 months of age. Overall, in addition to generating a novel murine model that phenotypically resembles GM1-gangliosidosis, the first model of β-galactosidase deficiency with residual enzyme activity has been developed.",
keywords = "Gangliosidosis, Lysosomal disease, Mouse Model, Mucopolysaccharidosis",
author = "Przybilla, {Michael J.} and Li Ou and Tăbăran, {Alexandru Flaviu} and Xuntian Jiang and Rohini Sidhu and Kell, {Pamela J.} and Ory, {Daniel S.} and O'Sullivan, {M. Gerard} and Whitley, {Chester B.}",
year = "2019",
month = "2",
doi = "10.1016/j.ymgme.2018.11.002",
language = "English (US)",
volume = "126",
pages = "139--150",
journal = "Molecular Genetics and Metabolism",
issn = "1096-7192",
publisher = "Academic Press Inc.",
number = "2",

}

TY - JOUR

T1 - Comprehensive behavioral and biochemical outcomes of novel murine models of GM1-gangliosidosis and Morquio syndrome type B

AU - Przybilla, Michael J.

AU - Ou, Li

AU - Tăbăran, Alexandru Flaviu

AU - Jiang, Xuntian

AU - Sidhu, Rohini

AU - Kell, Pamela J.

AU - Ory, Daniel S.

AU - O'Sullivan, M. Gerard

AU - Whitley, Chester B.

PY - 2019/2

Y1 - 2019/2

N2 - Deficiencies in the lysosomal hydrolase β-galactosidase (β-gal) lead to two distinct diseases: the skeletal disease Morquio syndrome type B, and the neurodegenerative disease GM1-gangliosidosis. Utilizing CRISPR-Cas9 genome editing, the mouse β-gal encoding gene, Glb1, was targeted to generate both models of β-gal deficiency in a single experiment. For Morquio syndrome type B, the common human missense mutation W273L (position 274 in mice) was introduced into the Glb1 gene (Glb1 W274L ), while for GM1-gangliosidosis, a 20 bp mutation was generated to remove the catalytic nucleophile of β-gal (β-gal −/− ). Glb1 W274L mice showed a significant reduction in β-gal enzyme activity (8.4–13.3% of wildtype), but displayed no marked phenotype after one year. In contrast, β-gal −/− mice were devoid of β-gal enzyme activity (≤1% of wildtype), resulting in ganglioside accumulation and severe cellular vacuolation throughout the central nervous system (CNS). β-gal −/− mice also displayed severe neuromotor and neurocognitive dysfunction, and as the disease progressed, the mice became emaciated and succumbed to the disease by 10 months of age. Overall, in addition to generating a novel murine model that phenotypically resembles GM1-gangliosidosis, the first model of β-galactosidase deficiency with residual enzyme activity has been developed.

AB - Deficiencies in the lysosomal hydrolase β-galactosidase (β-gal) lead to two distinct diseases: the skeletal disease Morquio syndrome type B, and the neurodegenerative disease GM1-gangliosidosis. Utilizing CRISPR-Cas9 genome editing, the mouse β-gal encoding gene, Glb1, was targeted to generate both models of β-gal deficiency in a single experiment. For Morquio syndrome type B, the common human missense mutation W273L (position 274 in mice) was introduced into the Glb1 gene (Glb1 W274L ), while for GM1-gangliosidosis, a 20 bp mutation was generated to remove the catalytic nucleophile of β-gal (β-gal −/− ). Glb1 W274L mice showed a significant reduction in β-gal enzyme activity (8.4–13.3% of wildtype), but displayed no marked phenotype after one year. In contrast, β-gal −/− mice were devoid of β-gal enzyme activity (≤1% of wildtype), resulting in ganglioside accumulation and severe cellular vacuolation throughout the central nervous system (CNS). β-gal −/− mice also displayed severe neuromotor and neurocognitive dysfunction, and as the disease progressed, the mice became emaciated and succumbed to the disease by 10 months of age. Overall, in addition to generating a novel murine model that phenotypically resembles GM1-gangliosidosis, the first model of β-galactosidase deficiency with residual enzyme activity has been developed.

KW - Gangliosidosis

KW - Lysosomal disease

KW - Mouse Model

KW - Mucopolysaccharidosis

UR - http://www.scopus.com/inward/record.url?scp=85057773844&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85057773844&partnerID=8YFLogxK

U2 - 10.1016/j.ymgme.2018.11.002

DO - 10.1016/j.ymgme.2018.11.002

M3 - Article

C2 - 30528226

AN - SCOPUS:85057773844

VL - 126

SP - 139

EP - 150

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

SN - 1096-7192

IS - 2

ER -