Galactosylceramidase deficiency causes sperm abnormalities in the mouse model of globoid cell leukodystrophy

Luddi, Alice; Strazza, Michelina; Carbone, Marica; Moretti, Elena; Costantino-Ceccarini, Elvira

doi:10.1016/j.yexcr.2004.10.034

Cited by 17 publications

(21 citation statements)

References 32 publications

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“…Previous studies have shown sperm abnormalities in twi mice. 43 Although there is no evidence for transduction of gonads, these mice can reproduce normally. Further studies are underway to investigate the health of gonads of male and female treated mice.…”

Section: Discussionmentioning

confidence: 98%

Extended Normal Life After AAVrh10-mediated Gene Therapy in the Mouse Model of Krabbe Disease

et al. 2012

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Globoid cell leukodystrophy (GLD) or Krabbe disease is a neurodegenerative disorder caused by the deficiency of the lysosomal enzyme galactocerebrosidase (GALC). This deficiency results in accumulation of certain galactolipids including psychosine which is cytotoxic for myelin-producing cells. Treatment of human patients at this time is limited to hematopoietic stem cell transplantation (HSCT) that appears to slow the progression of the disease when performed in presymptomatic patients. In this study, adeno-associated virus (AAV) serotype rh10-(AAVrh10) expressing mouse GALC was used in treating twitcher (twi) mice, the mouse model of GLD. The combination of intracerebroventricular, intracerebellar, and intravenous (iv) injection of viral particles in neonate twi mice resulted in high GALC activity in brain and cerebellum and moderate to high GALC activity in spinal cord, sciatic nerve, and some peripheral organs. Successfully treated mice maintained their weight with no or very little twitching, living up to 8 months. The physical activities of the long-lived treated mice were comparable to wild type for most of their lives. Treated mice showed normal abilities to mate, to deliver pups, to nurse and to care for the newborns. This strategy alone or in combination with other therapeutic options may be applicable to treatment of human patients.

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Section: Discussionmentioning

confidence: 98%

Extended Normal Life After AAVrh10-mediated Gene Therapy in the Mouse Model of Krabbe Disease

et al. 2012

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“…From significant marker rs42438348, in a distance of 61.570 bp, GALC gene is mapped, which codes galactosylceramidase, an enzyme responsible for hydrolysis of the terminal galactose from seminolipids precursors, specifically expressed in the membrane of germ cells (Piomboni et al, 2014). Luddi et al (2005) provided evidence that GALC plays important function in spermiogenesis and indicated on critical role for lysosomal enzymes in testicular as well as epididymal maturation of the mouse spermatozoa. In the close neighborhood of DCP1A, PRKCD gene (protein kinase C, delta) is located, which is expressed in mouse spermatogonia and may play role in spermatogenesis (Um et al, 1995) and be involved in various signaling pathways such as spermatogenesis and embryogenesis development (Suh et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study for semen volume and total number of sperm in Holstein-Friesian bulls

Hering

Oleński

Ruść

et al. 2014

Animal Reproduction Science

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“…Strikingly, when sperm from heterozygous ASMKO mice was used for in vitro fertilization of heterozygous oocytes followed by implantation into pseudopregnant wild-type mice, 37.8% of the resulting offspring were normal and 15.6% of the offspring were ASMKO affected mice [47]. Also, mice heterozygous for the βgal knockout mutation produced offspring of which 18% were affected by G M1 gangliosidosis [44], and sperm abnormalities have been reported in the mouse models of Niemann-Pick Disease type C [48] and globoid cell leukodystrophy (Twitcher mouse) [49].…”

Section: Discussionmentioning

confidence: 99%

Molecular consequences of the pathogenic mutation in feline GM1 gangliosidosis

Martin

Rigat

Foureman

et al. 2008

Molecular Genetics and Metabolism

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G M1 gangliosidosis is an inherited, fatal neurodegenerative disease caused by deficiency of lysosomal β-D-galactosidase (EC 3.2.1.23) and consequent storage of undegraded G M1 ganglioside. To characterize the genetic mutation responsible for feline G M1 gangliosidosis, the normal sequence of feline β-galactosidase cDNA first was defined. The feline β-galactosidase open reading frame is 2010 base pairs, producing a protein of 669 amino acids. The putative signal sequence consists of amino acids 1-24 of the β-galactosidase precursor protein, which contains seven potential N-linked glycosylation sites, as in the human protein. Overall sequence homology between feline and human β-galactosidase is 74% for the open reading frame and 82% for the amino acid sequence. After normal β-galactosidase was sequenced, the mutation responsible for feline G M1 gangliosidosis was defined as a G to C substitution at position 1448 of the open reading frame, resulting in an amino acid substitution at arginine 483, known to cause G M1 gangliosidosis in humans. Feline β-galactosidase messenger RNA levels were normal in cerebral cortex, as determined by quantitative RT-PCR assays. Although enzymatic activity is severely reduced by the mutation, a full-length feline β-galactosidase cDNA restored activity in transfected G M1 fibroblasts to 18-times normal. β-Galactosidase protein levels in G M1 tissues were normal on Western blots, but immunofluorescence analysis demonstrated that the majority of mutant β-galactosidase protein did not reach the lysosome. Additionally, G M1 cat fibroblasts demonstrated increased expression of glucose-related protein 78/BiP and protein disulfide isomerase, suggesting that the unfolded protein response plays a role in pathogenesis of feline G M1 gangliosidosis. CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptThe lysosomal enzyme β-D-galactosidase (βgal, EC 3.2.1.23) cleaves terminal galactose residues from a variety of molecules, including gangliosides G A1 and G M1 . Deficiency of βgal is known to cause two lysosomal storage diseases: G M1 gangliosidosis (neuronopathic) and Morquio B Disease (mucopolysaccharidosis IVB, non-neuronopathic [3,4]. Although the in vivo biochemical effect of the Arg482His mutation often is difficult to discern because it occurs most frequently in compound heterozygotes, patients homozygous for the G1445A substitution present with the infantile (most severe) form of G M1 gangliosidosis [3,7,8]. A similar mutation, Arg482Cys, also produced no residual βgal activity after expression in G M1 gangliosidosis fibroblasts [4].Feline G M1 gangliosidosis, first described in a Siamese cat in 1971 [9], models the juvenile form of the human disease. Onset of clinical neurological disease in affected cats occurs at approximately 3.5 months of age with a fine head or limb tremor. G M1 mutant cats have progressive dysmetria and ambulatory difficulties, with blindness and epileptiform seizures in the terminal disease stage at 9-10 months of age. In the current st...

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Galactosylceramidase deficiency causes sperm abnormalities in the mouse model of globoid cell leukodystrophy

Cited by 17 publications

References 32 publications

Extended Normal Life After AAVrh10-mediated Gene Therapy in the Mouse Model of Krabbe Disease

Extended Normal Life After AAVrh10-mediated Gene Therapy in the Mouse Model of Krabbe Disease

Genome-wide association study for semen volume and total number of sperm in Holstein-Friesian bulls

Molecular consequences of the pathogenic mutation in feline GM1 gangliosidosis

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