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Neurogenetics: white matter matters
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However, previous results obtained with the haplo-diploid mite Brevipalpus phoenicis (see Weeks et al. in Ref. [1]) suggest an alternative explanation. In this species, a bacterium, closely related to EB, forces unfertilized eggs to develop as haploid females. Could it be that EB and its close relatives are specialized in hostfeminization, the process by which endocellular symbionts induce female development without manipulating chromosomes? On the basis of this speculative hypothesis, one might propose the following evolutionary scenario. Feminizing bacteria might infect both diploid and haplo-diploid species. In diploids, although advantageous in the
TRENDS in Genetics Vol.18 No.2 February 2002
short term, this strategy is suicidal for the symbiont; as males get very rare, host populations are likely to go extinct (note, this does not keep Wolbachia-induced feminization from occurring in diploids). By contrast, feminization is viable in the long term in haplo-diploids: males are also lost in this case, but extinction risk is not increased. Feminization in haplo-diploids would result, as in Brevipalpus, in unfertilized eggs developing as haploid females, inducing a shift from arrhenotokous to thelytokous parthenogenesis, without affecting ploidy. Because diploidy limits the deleterious effects of recessive mutations, gamete duplication (or some other mechanisms
71
restoring diploidy) might, in some cases, evolve secondarily, without being the primary cause of female development. Under this view, parthenogenesis induction would simply be a sort of successful feminization, viable in the long term. 1 Zchori-Fein, E. et al. (2001) A newly discovered bacterium associated with parthenogenesis and a change in host selection behavior in parasitoid wasps. Proc. Natl. Acad. Sci. U. S. A. 98, 12555–12560
Sylvain Charlat [email protected] Hervé Merçot [email protected]
Neurogenetics: white matter matters A group of inherited syndromes characterized by progressive muscle atrophy and sensory dysfunction, collectively referred to as Charcot–Marie–Tooth disease (CMT), has proven to be a hotbed for the identification of novel genetic mutations. CMT syndromes are unusually common (affecting one in every 2200 people), can be dominant, recessive or X-linked, and involve demyelination and axonal damage. In two recent articles, Baxter et al. [1] and Cuesta et al. [2] identify the genetic defect responsible for a novel recessive CMT syndrome called CMT4A. The genetic defect responsible for CMT4A was mapped to chromosome 8 and mutations in the gene encoding ganglioside-induced differentiation-associated protein-1 (GDAP1) were established as the disease-causing alterations. GDAP1 is expressed in both the peripheral (PNS) and central (CNS) nervous systems where it can be present at particularly high levels in Schwann cells and oligodendrocytes; levels increase during development and are highest in the adult. GDAP1 encodes a protein with two transmembrane domains and a region that contains a glutathione-S-transferase (GST) domain. GSTs are known to function in antioxidant pathways and in detoxification, and GDAP1 appears to contain a glutathionebinding site in a thioredoxin-like fold domain adjacent to an α-helical domain that might recognize xenobiotic substrates. Its presumptive antioxidant/detoxification properties might have a role in protecting myelin membranes against free radicalmediated damage, to which it is susceptible. http://tig.trends.com
A remarkable number of genes have been linked to CMT syndromes. The most frequent alteration is duplication of the gene encoding peripheral myelin protein-22 (pmp22), believed to impair myelin formation by an unknown mechanism. Mutations in the gap junction protein connexin-32 are responsible for other cases of CMT, presumably as the result of impaired coupling between Schwann cells or between myelin membranes of the same cell. The transcription factor EGR2 can harbor CMT-linked mutations and can cause demyelination by impairing differentiation of Schwann cells. Other genes linked to CMT include N-myc downstream regulated gene 1 and the genes encoding myotubularin (a phosphatase) and periaxin (a PDZ domain protein). How can alterations in these seemingly unrelated genes result in a similar clinical phenotype? GDAP1, pmp22 and connexin-32 are each membrane-associated proteins that might affect the integrity and/or function of myelin. EGR2 was recently shown to be important in regulating the expression of connexin-32, suggesting a mechanistic link between these two genes and CMT; gap junctions might be required for both the formation and maintenance of myelin sheaths. Gap junctional communication can protect cells against oxidative stress, pointing to shared pathogenic mechanisms of GDAP1, connexin-32 and EGR2 mutations. The fact that CMT syndromes mainly affect peripheral nerves, with less
involvement of myelinated axons within the CNS, suggests that there are aspects of myelination that are unique to the PNS. Among the genes linked to CMT, some might be expressed only in Schwann cells and not in oligodendrocytes (pmp22 and periaxin), whereas others are present in both types of myelinating cells (connexin-32 and GDAP1). The selective involvement of peripheral nerves might therefore be explained by specific properties of Schwann cells related to membrane interactions involving pmp22 and periaxin that are linked to alterations in gap junctional communication and oxidative damage to membranes. The history of CMT research is exemplary of the power of molecular genetics in rapidly advancing knowledge of disease processes and in revealing the normal functions of novel genes. A better understanding of the functions of these genes will provide clues as to the cellular and molecular cascades that result in dysfunction and degeneration of white matter cells in an array of neurological disorders. 1 Baxter, R. V. et al. (2001) Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot–Marie–Tooth disease type 4A/8q21. Nat. Genet. 30, 21–22 2 Cuesta, A. et al. (2001) The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot–Marie–Tooth type 4A disease. Nat. Genet. 30, 22–25
Mark P. Mattson [email protected]
0168-9525/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
However, previous results obtained with the haplo-diploid mite Brevipalpus phoenicis (see Weeks et al. in Ref. [1]) suggest an alternative explanation. In this species, a bacterium, closely related to EB, forces unfertilized eggs to develop as haploid females. Could it be that EB and its close relatives are specialized in hostfeminization, the process by which endocellular symbionts induce female development without manipulating chromosomes? On the basis of this speculative hypothesis, one might propose the following evolutionary scenario. Feminizing bacteria might infect both diploid and haplo-diploid species. In diploids, although advantageous in the
TRENDS in Genetics Vol.18 No.2 February 2002
short term, this strategy is suicidal for the symbiont; as males get very rare, host populations are likely to go extinct (note, this does not keep Wolbachia-induced feminization from occurring in diploids). By contrast, feminization is viable in the long term in haplo-diploids: males are also lost in this case, but extinction risk is not increased. Feminization in haplo-diploids would result, as in Brevipalpus, in unfertilized eggs developing as haploid females, inducing a shift from arrhenotokous to thelytokous parthenogenesis, without affecting ploidy. Because diploidy limits the deleterious effects of recessive mutations, gamete duplication (or some other mechanisms
71
restoring diploidy) might, in some cases, evolve secondarily, without being the primary cause of female development. Under this view, parthenogenesis induction would simply be a sort of successful feminization, viable in the long term. 1 Zchori-Fein, E. et al. (2001) A newly discovered bacterium associated with parthenogenesis and a change in host selection behavior in parasitoid wasps. Proc. Natl. Acad. Sci. U. S. A. 98, 12555–12560
Sylvain Charlat [email protected] Hervé Merçot [email protected]
Neurogenetics: white matter matters A group of inherited syndromes characterized by progressive muscle atrophy and sensory dysfunction, collectively referred to as Charcot–Marie–Tooth disease (CMT), has proven to be a hotbed for the identification of novel genetic mutations. CMT syndromes are unusually common (affecting one in every 2200 people), can be dominant, recessive or X-linked, and involve demyelination and axonal damage. In two recent articles, Baxter et al. [1] and Cuesta et al. [2] identify the genetic defect responsible for a novel recessive CMT syndrome called CMT4A. The genetic defect responsible for CMT4A was mapped to chromosome 8 and mutations in the gene encoding ganglioside-induced differentiation-associated protein-1 (GDAP1) were established as the disease-causing alterations. GDAP1 is expressed in both the peripheral (PNS) and central (CNS) nervous systems where it can be present at particularly high levels in Schwann cells and oligodendrocytes; levels increase during development and are highest in the adult. GDAP1 encodes a protein with two transmembrane domains and a region that contains a glutathione-S-transferase (GST) domain. GSTs are known to function in antioxidant pathways and in detoxification, and GDAP1 appears to contain a glutathionebinding site in a thioredoxin-like fold domain adjacent to an α-helical domain that might recognize xenobiotic substrates. Its presumptive antioxidant/detoxification properties might have a role in protecting myelin membranes against free radicalmediated damage, to which it is susceptible. http://tig.trends.com
A remarkable number of genes have been linked to CMT syndromes. The most frequent alteration is duplication of the gene encoding peripheral myelin protein-22 (pmp22), believed to impair myelin formation by an unknown mechanism. Mutations in the gap junction protein connexin-32 are responsible for other cases of CMT, presumably as the result of impaired coupling between Schwann cells or between myelin membranes of the same cell. The transcription factor EGR2 can harbor CMT-linked mutations and can cause demyelination by impairing differentiation of Schwann cells. Other genes linked to CMT include N-myc downstream regulated gene 1 and the genes encoding myotubularin (a phosphatase) and periaxin (a PDZ domain protein). How can alterations in these seemingly unrelated genes result in a similar clinical phenotype? GDAP1, pmp22 and connexin-32 are each membrane-associated proteins that might affect the integrity and/or function of myelin. EGR2 was recently shown to be important in regulating the expression of connexin-32, suggesting a mechanistic link between these two genes and CMT; gap junctions might be required for both the formation and maintenance of myelin sheaths. Gap junctional communication can protect cells against oxidative stress, pointing to shared pathogenic mechanisms of GDAP1, connexin-32 and EGR2 mutations. The fact that CMT syndromes mainly affect peripheral nerves, with less
involvement of myelinated axons within the CNS, suggests that there are aspects of myelination that are unique to the PNS. Among the genes linked to CMT, some might be expressed only in Schwann cells and not in oligodendrocytes (pmp22 and periaxin), whereas others are present in both types of myelinating cells (connexin-32 and GDAP1). The selective involvement of peripheral nerves might therefore be explained by specific properties of Schwann cells related to membrane interactions involving pmp22 and periaxin that are linked to alterations in gap junctional communication and oxidative damage to membranes. The history of CMT research is exemplary of the power of molecular genetics in rapidly advancing knowledge of disease processes and in revealing the normal functions of novel genes. A better understanding of the functions of these genes will provide clues as to the cellular and molecular cascades that result in dysfunction and degeneration of white matter cells in an array of neurological disorders. 1 Baxter, R. V. et al. (2001) Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot–Marie–Tooth disease type 4A/8q21. Nat. Genet. 30, 21–22 2 Cuesta, A. et al. (2001) The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot–Marie–Tooth type 4A disease. Nat. Genet. 30, 22–25
Mark P. Mattson [email protected]
0168-9525/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.