Gene for Wilson's disease
1
1481 Cell suicide gene cloned Researchers at the Massachusetts Institute of Technology (MIT) have cloned a sui- cide gene responsible for programmed cell death, or apoptosis, in the roundworm Caenorhabditis elegans, and, in a related study, scientists at Massachusetts General Hospital (MGH) demonstrated that a similar mammalian gene will cause pro- grammed cell death in rat fibroblast cells. Junying Yuan, who worked with both research teams, said the findings should advance the understanding of the role of programmed cell death in embryonic development, tissue homoeostasis, inflam- mation, and disease. In the first paper, MIT researchers reported that they cloned ced-3, a gene essential for programmed cell death in C elegans. Then, by working with the sequences of the cloned cDNA, they deduced that the gene’s product is a 503 aminoacid protein whose active site is similar to that of interleukin-1-converting enzyme (ICE). ICE, a cysteine protease, cleaves the inactive precursor of IL-1 to generate the active cytokine. High levels of IL-L have been detected in Alzheimer’s disease, rheumatoid arthritis, septic shock, and head injury. The active site of the ced-3 protein was also similar to the pro- t tein product of the mouse gene nedd-2, 1 which is expressed during embryonic ! brain development and then down-regu- ( lated in the adult. , In a follow-on study to the MIT lab’s 1 work, researchers at MGH joined a pro- i moter gene to the gene for murine ICE, 1 introduced it into rat fibroblasts, and found that overexpression of ICE caused 1 stereotypical programmed cell death in these mammalian cells. In addition, they found that the mammalian proto-onco- gene bcl-2 and the viral gene crm-A could inhibit the cell death brought on by the overexpression of ICE gene. The researchers concluded, first, that the ced-3 protease acts to control pro- grammed cell death in C elegans and, sec- ond, that members of the ced-3fICE/ nedd-2 gene family might function in pro- grammed cell death in vertebrates. The inhibitory effect of bcl-2 suggests that not only does bcl-2 act to regulate cell death but also that the gene for ICE and other members of the ced-3fICE family could be recessive oncogenes, whose elimination could prevent normal cell death and pro- mote malignancy. The finding that the viral gene crm-A inhibits ICE-induced cell death suggests that one way an infecting virus may pro- long its host-cell’s life is by preventing its suicide. "It is definitely to the advantage of the virus to have the cell live longer", said Yuan. ICE, therefore, in addition to eliciting immune response to viral infection by activating IL-1, could also be initiating the suicide of infected cells, Yuan said, "so one stone kills two birds". MIT researcher Shai Shaham said one focus of future research will be to identify sequences crucial to the func- tion of ICE and related proteins. "Not only would this have implications for blocking or inactivating cell death in humans", Shaham said, "it could also be very useful in designing drugs that might interfere with ICE in its role in inflammation". 1 Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. The C elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1-converting enzyme. Cell 1993; 75: 1-20. 2 Miura M, Zhu H, Rotello R, Hartwieg EA, Yuan J. Induction of apoptosis in fibroblasts by IL-1-converting enzyme, a mammalian homolog of the C elegans cell death gene ced-3. Cell 1993; 75: 653-60. Michael McCarthy Gene for Wilson’s disease Wilson’s disease (hepatolenticular degen- eration) is an autosomal recessive disorder characterised by accumulation of copper in the liver and, when binding sites there are saturated, in the brain, cornea, and kidneys. The underlying biochemical abnormalities are reduced incorporation of copper into caeruloplasmin and defec- tive biliary excretion of copper. The disor- der can be treated effectively with penicillamine but is fatal if left untreated. Wilson’s disease is a classic example of an inborn error of metabolism. The gene that causes it has now been dissected.’-3 Linkage studies had already assigned the Wilson’s disease locus (WD) to chro- mosome 13ql4-3, and the impetus to define its position more precisely came partly from the recent isolation of the gene for Menkes’ disease (MNK), an X-linked disorder of copper metabolism. Although Wilson’s disease is primarily a defect of liver function, whereas the MNK gene is expressed in all tissues except the liver, the identification of the normal (wild-type) = MNK gene product as a copper-transport- ing P-type ATPase suggested that Wil- son’s disease might also be caused by a defect in a copper transporter. Cox et al used a probe from the proposed copper- binding region of the MNK gene to search for a homologue on 13ql4-3. The result was the identification of a region some 30 kb long showing nearly 60% homology with AfA’7’C.’Tanzi et al used a different technique to isolate the WD gene and found a similar degree of homology with MNK.3 Tanzi’s DNA sequence analysis revealed four disease-specific single-base- pair mutations within the WD gene, three being found in only one or two affected members among 115 families studied.3 Tanzi et al predict difficulties with DNA- based genetic diagnosis because they expect more mutations to be found. For the present, screening of patients’ families will continue to be based on biochemical tests. In the short term the most likely benefit from isolating the WD and MNK genes will be a better understanding of the molecular basis of copper homoeosta- sis. One question is why two structurally similar genes have apparently paradoxical effects: the MNK gene’s normal function appears to be to ensure that dietary cop- per is distributed to all tissues that need it, whereas the wild-type WD gene protects against excessive copper accumulation. Dorothy Bonn 1 Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nature Genet 1993; 5: 327-37. 2 Petrukhin K, Fischer SG, Pirastu M, et al. Mapping, cloning and genetic characterization of the region containing the Wilson disease gene. Nature Genet 1993; 5: 338-43. 3 Tanzi RE, Petrukhin K, Chemov I, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes gene. Nature Genet 1993; 5: 345-50. Bioethics convention Agreement on the European Bioethics Convention, the first accord of its kind, should be clinched by the end of 1994, two years later than originally envisaged, says the Council of Europe. Latest details were given at the Council’s second sym- posium on bioethics in Strasbourg, Nov 30-Dec 2. (This meeting coincided with WHO call for international consultations to secure a consensus on guidelines for research in genetics and biotechnology.) A pragmatic approach is being taken on a text that seeks to cover a subject in which national divergence and technical progress appear to be running ahead of the Stras- bourg organisation’s efforts at harmonisa- tion. The latest draft is a distillation of uncontroversial general principles such as free and informed consent and adherence to professional standards. Many of these are already the subject of non-binding Council of Europe recommendations. The specific issues of organ transplanta- tion and medical research will be covered in separate protocols, although the latter text has yet to be agreed within the Con- vention’s main steering committee. Later, the Convention may be joined by a third specific protocol on the protection of the human embryo and fetus, but drafting has been postponed. In other areas, member states still dif- fer. While unanimously agreeing that interventions on the human genome should have a therapeutic or diagnostic
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Transcript of Gene for Wilson's disease
1481
Cell suicide gene cloned
Researchers at the Massachusetts Instituteof Technology (MIT) have cloned a sui-cide gene responsible for programmed celldeath, or apoptosis, in the roundworm
Caenorhabditis elegans, and, in a related
study, scientists at Massachusetts GeneralHospital (MGH) demonstrated that a
similar mammalian gene will cause pro-grammed cell death in rat fibroblast cells.Junying Yuan, who worked with both
research teams, said the findings shouldadvance the understanding of the role ofprogrammed cell death in embryonicdevelopment, tissue homoeostasis, inflam-mation, and disease.
In the first paper, MIT researchers
reported that they cloned ced-3, a geneessential for programmed cell death inC elegans. Then, by working with the
sequences of the cloned cDNA, theydeduced that the gene’s product is a 503aminoacid protein whose active site is
similar to that of interleukin-1-convertingenzyme (ICE). ICE, a cysteine protease,cleaves the inactive precursor of IL-1 to
generate the active cytokine. High levels ofIL-L have been detected in Alzheimer’s
disease, rheumatoid arthritis, septic shock,and head injury. The active site of the
ced-3 protein was also similar to the pro- t
tein product of the mouse gene nedd-2, 1which is expressed during embryonic !
brain development and then down-regu- (
lated in the adult. ,
In a follow-on study to the MIT lab’s 1
work, researchers at MGH joined a pro- imoter gene to the gene for murine ICE, 1
introduced it into rat fibroblasts, andfound that overexpression of ICE caused 1
stereotypical programmed cell death inthese mammalian cells. In addition, theyfound that the mammalian proto-onco-gene bcl-2 and the viral gene crm-A couldinhibit the cell death brought on by theoverexpression of ICE gene.The researchers concluded, first, that
the ced-3 protease acts to control pro-
grammed cell death in C elegans and, sec-ond, that members of the ced-3fICE/nedd-2 gene family might function in pro-grammed cell death in vertebrates. The
inhibitory effect of bcl-2 suggests that notonly does bcl-2 act to regulate cell deathbut also that the gene for ICE and other
members of the ced-3fICE family could berecessive oncogenes, whose elimination
could prevent normal cell death and pro-mote malignancy.The finding that the viral gene crm-A
inhibits ICE-induced cell death suggests
that one way an infecting virus may pro-long its host-cell’s life is by preventing itssuicide. "It is definitely to the advantageof the virus to have the cell live longer",said Yuan. ICE, therefore, in additionto eliciting immune response to viral
infection by activating IL-1, could alsobe initiating the suicide of infected cells,Yuan said, "so one stone kills two
birds".
MIT researcher Shai Shaham saidone focus of future research will be to
identify sequences crucial to the func-tion of ICE and related proteins. "Notonly would this have implications for
blocking or inactivating cell death in
humans", Shaham said, "it could alsobe very useful in designing drugs thatmight interfere with ICE in its role ininflammation".
1 Yuan J, Shaham S, Ledoux S, Ellis HM,Horvitz HR. The C elegans cell deathgene ced-3 encodes a protein similar tomammalian interleukin-1-convertingenzyme. Cell 1993; 75: 1-20.
2 Miura M, Zhu H, Rotello R, Hartwieg EA,Yuan J. Induction of apoptosis in fibroblastsby IL-1-converting enzyme, a mammalianhomolog of the C elegans cell death geneced-3. Cell 1993; 75: 653-60.
Michael McCarthy
Gene for Wilson’s disease
Wilson’s disease (hepatolenticular degen-eration) is an autosomal recessive disordercharacterised by accumulation of copperin the liver and, when binding sites thereare saturated, in the brain, cornea, andkidneys. The underlying biochemicalabnormalities are reduced incorporationof copper into caeruloplasmin and defec-tive biliary excretion of copper. The disor-der can be treated effectively with
penicillamine but is fatal if left untreated.Wilson’s disease is a classic example of aninborn error of metabolism. The gene thatcauses it has now been dissected.’-3
Linkage studies had already assignedthe Wilson’s disease locus (WD) to chro-mosome 13ql4-3, and the impetus to
define its position more precisely camepartly from the recent isolation of the genefor Menkes’ disease (MNK), an X-linkeddisorder of copper metabolism. AlthoughWilson’s disease is primarily a defect ofliver function, whereas the MNK gene is
expressed in all tissues except the liver, theidentification of the normal (wild-type) =MNK gene product as a copper-transport-ing P-type ATPase suggested that Wil-
son’s disease might also be caused by adefect in a copper transporter. Cox et alused a probe from the proposed copper-binding region of the MNK gene to searchfor a homologue on 13ql4-3. The resultwas the identification of a region some 30kb long showing nearly 60% homologywith AfA’7’C.’Tanzi et al used a different
technique to isolate the WD gene and
found a similar degree of homology withMNK.3
Tanzi’s DNA sequence analysisrevealed four disease-specific single-base-pair mutations within the WD gene, threebeing found in only one or two affectedmembers among 115 families studied.3Tanzi et al predict difficulties with DNA-based genetic diagnosis because theyexpect more mutations to be found. Forthe present, screening of patients’ familieswill continue to be based on biochemicaltests. In the short term the most likelybenefit from isolating the WD and MNKgenes will be a better understanding ofthe molecular basis of copper homoeosta-sis. One question is why two structurallysimilar genes have apparently paradoxicaleffects: the MNK gene’s normal functionappears to be to ensure that dietary cop-per is distributed to all tissues that need it,whereas the wild-type WD gene protectsagainst excessive copper accumulation.
Dorothy Bonn
1 Bull PC, Thomas GR, Rommens JM, ForbesJR, Cox DW. The Wilson disease gene is aputative copper transporting P-type ATPasesimilar to the Menkes gene. Nature Genet
1993; 5: 327-37.2 Petrukhin K, Fischer SG, Pirastu M, et al.Mapping, cloning and geneticcharacterization of the region containing theWilson disease gene. Nature Genet 1993; 5:338-43.
3 Tanzi RE, Petrukhin K, Chemov I, et al. TheWilson disease gene is a copper transportingATPase with homology to the Menkes gene.Nature Genet 1993; 5: 345-50.
Bioethics convention
Agreement on the European Bioethics
Convention, the first accord of its kind,should be clinched by the end of 1994,two years later than originally envisaged,says the Council of Europe. Latest detailswere given at the Council’s second sym-posium on bioethics in Strasbourg, Nov30-Dec 2. (This meeting coincided withWHO call for international consultationsto secure a consensus on guidelines forresearch in genetics and biotechnology.) Apragmatic approach is being taken on atext that seeks to cover a subject in whichnational divergence and technical progressappear to be running ahead of the Stras-bourg organisation’s efforts at harmonisa-tion. The latest draft is a distillation of
uncontroversial general principles such asfree and informed consent and adherenceto professional standards. Many of theseare already the subject of non-bindingCouncil of Europe recommendations.The specific issues of organ transplanta-tion and medical research will be coveredin separate protocols, although the lattertext has yet to be agreed within the Con-vention’s main steering committee. Later,the Convention may be joined by a thirdspecific protocol on the protection of thehuman embryo and fetus, but drafting hasbeen postponed.
In other areas, member states still dif-
fer. While unanimously agreeing thatinterventions on the human genomeshould have a therapeutic or diagnostic
