Sperm Abnormalities in Heterozygous Acid Sphingomyelinase Knockout Mice Reveal a Novel Approach for the Prevention of Genetic Diseases

Butler, Avigdor; Gordon, Ronald E.; Gátt, Shimon; Schuchman, Edward H.

doi:10.2353/ajpath.2007.061002

Cited by 22 publications

(16 citation statements)

References 49 publications

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“…Through regulated secretion and reabsorption, they control the pH, osmotic pressure, and composition of epididymal fluids and also the transfer of metabolites such as proteins, sugars, and lipids to and from the sperm surface. Interactions with the proximal epididymis are essential for the acquisition of fertilizing ability by sperm, and alteration of the genes encoding several proteins secreted from the epididymal epithelium often leads to male infertility as a result of defective sperm motility or morphology (10,42,(56)(57)(58)(59). We found that sPLA 2 -III is expressed in the proximal epididymal epithelium and secreted into the luminal fluid (Figures 1 and 2), that spermatozoa of Pla2g3 -/-mice are numerically normal but functionally and structurally abnormal (Figures 3-5), and that epididymal sperm of Pla2g3 -/-mice have an altered phospholipid composition ( Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Group III secreted phospholipase A2 regulates epididymal sperm maturation and fertility in mice

Sato¹,

Taketomi²,

Isogai³

et al. 2010

J. Clin. Invest.

107

106

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Although lipid metabolism is thought to be important for the proper maturation and function of spermatozoa, the molecular mechanisms that underlie this dynamic process in the gonads remains incompletely understood. Here, we show that group III phospholipase A 2 (sPLA 2 -III), a member of the secreted phospholipase A 2 (sPLA 2 ) family, is expressed in the mouse proximal epididymal epithelium and that targeted disruption of the gene encoding this protein (Pla2g3) leads to defects in sperm maturation and fertility. Although testicular spermatogenesis in Pla2g3 -/-mice was grossly normal, spermatozoa isolated from the cauda epididymidis displayed hypomotility, and their ability to fertilize intact eggs was markedly impaired. Transmission EM further revealed that epididymal spermatozoa in Pla2g3 -/-mice had both flagella with abnormal axonemes and aberrant acrosomal structures. During epididymal transit, phosphatidylcholine in the membrane of Pla2g3 +/+ sperm underwent a dramatic shift in its acyl groups from oleic, linoleic, and arachidonic acids to docosapentaenoic and docosahexaenoic acids, whereas this membrane lipid remodeling event was compromised in sperm from Pla2g3 -/-mice. Moreover, the gonads of Pla2g3 -/-mice contained less 12/15-lipoxygenase metabolites than did those of Pla2g3 +/+ mice. Together, our results reveal a role for the atypical sPLA 2 family member sPLA 2 -III in epididymal lipid homeostasis and indicate that its perturbation may lead to sperm dysfunction.

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Section: Discussionmentioning

confidence: 99%

Group III secreted phospholipase A2 regulates epididymal sperm maturation and fertility in mice

Sato¹,

Taketomi²,

Isogai³

et al. 2010

J. Clin. Invest.

107

106

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“…Although they produced normal numbers of sperm, heterozygotes demonstrated abnormal sperm morphology, mitochondrial membrane potential and ability to undergo capacitation or the acrosome reaction. 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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“…The generation of such Cer from SM as precursor requires either (i) a form of SMase that is specifi c for 2-OH VLCPUFA-containing species of SM, or (ii) an ordinary SMase that expresses itself in a cell-specifi c manner in spermatids. Mice defi cient in acid SMase in their lysosomes (a model of the human Niemann-Pick disease), accumulate SM in their tissues, including testis (mostly as lipid inclusions in Sertoli cells), and produce spermatozoa that develop an abnormal motility (40)(41)(42). The latter of these defects correlated with an excess of surface area in the midpiece of the sperm tail in late spermatids and spermatozoa, with the mature gametes showing a rigid bending of their tails that preclude normal motility.…”

Section: Germ Cell-neutral Lipidsmentioning

confidence: 99%

Differentiation-related changes in lipid classes with long-chain and very long-chain polyenoic fatty acids in rat spermatogenic cells

Oresti

Reyes

Luquez

et al. 2010

Journal of Lipid Research

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Mammalian spermatogenesis is an extraordinary cell transformation process. It includes asymmetric division of spermatogonia, rapid proliferation and differentiation into primary spermatocytes, a meiotic phase in which the genetic material in spermatocytes is recombined and segregated to produce haploid cells, a postmeiotic phase in which secondary spermatocytes develop into round spermatids, and differentiation of the latter into late spermatids and spermatozoa ( 1 ). During this last stage, known as spermiogenesis, spermatids undergo relevant cytological transformations, with changes in nuclear shape, chromatin condensation, formation of acrosome and fl agellum, and disposal of surplus organelles and materials by production and release of membrane-enclosed remnants known as "residual bodies" ( 2, 3 ). These minute, densely packed particles are then engulfed by Sertoli cells ( 4 ).The sphingomyelin (SM) ( 5 ) and ceramide (Cer) ( 6 ) of cells located in mammalian seminiferous tubules are rich in very long chain (C24 to C34) polyunsaturated fatty acids (VLCPUFA) of the n-6 or the n-3 series, the main ones being 28:4n-6 and 30:5n-6, followed by 32:5n-6 in the rat. These lipids belong to spermatogenic cells, as indicated by the facts that i) in the prepubertal rat testis, VLCPUFAcontaining species of SM and Cer are not detected; ii) in

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Sperm Abnormalities in Heterozygous Acid Sphingomyelinase Knockout Mice Reveal a Novel Approach for the Prevention of Genetic Diseases

Cited by 22 publications

References 49 publications

Group III secreted phospholipase A2 regulates epididymal sperm maturation and fertility in mice

Group III secreted phospholipase A2 regulates epididymal sperm maturation and fertility in mice

Molecular consequences of the pathogenic mutation in feline GM1 gangliosidosis

Differentiation-related changes in lipid classes with long-chain and very long-chain polyenoic fatty acids in rat spermatogenic cells

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