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`GeneDX 1027, pg. 1
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`Nature Genetics
`
`Editorial Office
`1234 National
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`Deputy Editor
`Barbara J. Culliton
`(Washington)
`
`contents
`
`editorial Keeping track of the translocations
`neWS & VieWS Opening the gates on ion channel diseases
`
`John H Caldwell & Kristin L Schaller
`
`Breast cancer genes: how many, where
`rl- and who are they?
`Mary-Claire King
`
`correspondence
`
`A common origin for cornified envelope proteins
`C Backendorf & D Hohl
`
`revtew
`"
`articles
`
`A brief history of gene therapy
`Theodore Friedmann
`
`Mutations in the vasopressin type 2 receptor gene
`(A VPR2) associated with nephrogenic
`diabetes insipidus
`A M W van den Ouweland, J C F M Dreesen,
`M V erdijk, N VA M Knoers, L A H Monnens, M Rocchi
`&BAvan Oost
`
`Mutations in the V2 vasopressin receptor gene are
`associated with X-linked nephrogenic
`diabetes insipidus
`Y Pang, A Metzenberg, S Das, B Jing & J Gitschier
`
`Aberrant splicing of neural cell adhesion
`molecule L 1 mRNA in a family with
`X-linked hydrocephalus
`A Rosenthal, M Jouet & S Kenwrick
`
`A trithorax-like gene is interrupted by
`chromosome 11 q23 translocations in
`acute leukaemias
`M Djabali, L Selleri, P Parry, M Bower, B D Young
`&GAEvans
`
`Human homologs of a Drosophila Enhancer of
`Split gene product define a novel family of
`nuclear proteins
`S Stifani, C M Blaumueller, N J Redhead, R E Hill
`& S Artavanis-Tsakonas
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`Nature Genetics (ISSN 1 061 -4036) is published monthly by Nature Publishing Co., headquartered at65 Bleecker Street, New York,
`NY 10012, which is owned by Nature America Inc., a subsidiary of Macmillan Magazines Ltd., of London.Editorlal Office: Nature
`Genetics, 1234 National Press Building , Washington DC 20045. Telephone (202) 626 2513 Fax (202) 628 1609 North American
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`Officers of Nature America, Inc.: Nicholas Byam Shaw, Chairman of the Board ; Andy Sutherland, President; Edward Valis, Secretary(cid:173)
`Treasurer. Printed in the USA by William Byrd Press.© 1992 Nature America, Inc.
`
`Cover art: Model of triple helical DNA,
`courtesy of BIOSYM Technologies.
`
`nature genetics volume 2 october 1992
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`GeneDX 1027, pg. 2
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`news & views
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`normal and abnormal subunits, only
`25% of the channels (those with two
`normal subunits) would function
`properly. Thiswouldexplainhowone
`altered allele could have a severe effect
`upon chloride conductance. The
`discovery of this mutation in chloride
`channels does not rule out the
`involvement of sodium channels in
`some families with MC; one form of
`the disease has been genetically linked
`to the sodium channeJI 8
`•
`HYPP, PMC and myotonia
`congenita in other families are tightly
`linked to the sodium or chloride
`channel but do not seem to have any
`of the published mutations. Thus
`additional sodium and chloride
`channel mutations await discovery.
`Since potassium and calcium channels
`have a predicted secondary structure
`similar to sodium channels, it seems
`inevitable that point mutations in
`each of these channels will also cause
`human disease. Moreover, ion
`channels belong to multigene families,
`
`as illustrated in Table 1 for sodium
`channels. Five full length and two
`partial sodium channel sequences
`have
`been
`published,
`and
`unpublished reports of additional
`partial sequences indicate several
`more genes. Thus, the rat genome
`probably contains at least ten sodium
`channel genes, which may all possess
`a homologue in humans. All of the
`mutations in Fig. 1 a occur in a single
`
`gene, the one expressed in adult
`skeletal muscle. Many of the other
`human sodium channel genes are
`expressed in the nervous system.
`Mapping these genes will allow linkage
`studies to be done in families with
`nervous system disorders, and will
`help determine whether mutations in
`these genes conceivably produce
`epilepsy or other more subtle mental
`defects.
`D
`
`References
`1. Hille, B.lonic Channels of Excitable Membranes
`(Sinauer, Sunderland, Massachusetts, 1992).
`2. Ptacek, L.J. eta/. Ce//67, 1021-1027 (1991).
`3. Rojas, C.V. eta/. Nature 354, 387-389 (1991).
`4. McClatchey, A.l. et a/. Cell, 68, 769-774
`(1992).
`5. Ptacek, L.J. eta/. Neuron 8, 891-897 (1992).
`6. Rudolph , J.A. eta/. Nature Genet. 2, 144-147
`(1992).
`7. McCiatchey,A.I.eta/.NatureGenet. 2,148-152
`(1992).
`8. Lehmann-Horn, F. eta/. Muscle Nerve 10, 363-
`374 (1987).
`9. Cannon, S.C., Brown, A. H. &Corey, D.P.Neuron
`6, 619--626 (1991).
`10. Lehmann-Horn, F., laizzo, P.A., Hatt, H. &Franke,
`Ch. Pf/Ogers Arch. 418, 297-299 (1991).
`11 . Armstrong , C.M. & Bezanilla, F. J. Gen Physiol.
`70, 567-590 (1977).
`
`12. Hoshi, T. , Zagotta, W.N. &Aldrich, A.W. Science
`250, 533-538 (1990).
`13. Stohmer, W. eta/. Nature 339,597--603 (1989).
`14. Vassilev, P., Scheuer, T. & Catterall, W.A. Proc.
`natn. Acad. Sci. U.S.A. 86,8147-8151 (1989).
`15. Stohmer, W., &Parekh, A.B. Curr. Op. Neurobiol.
`2, 243-246 (1992).
`16. Jentsch, T.J., Steinmeyer, K. & Schwartz, G.
`Nature 348, 51Q-.514 (1990).
`17. Koch, M.G. eta/. Science 257,797-800 (1992).
`18. P1acek, L.J ., Tawil, A., Griggs, A. C., Storvick, D.
`& Leppert, M.F. Neural. 42, 431--433. (1992).
`19. Gautron, S. eta/. Proc. natn. Acad. Sci. U.S.A.
`89, 7272-7276 (1992).
`20. George,A.L., Knittle, T.J. & Tamkun, M.M. Proc.
`natn. Acad. Sci. U.S.A. 89, 4893--4897 (1992).
`21. Guy, H. A. & Conti, F. TINS 13, 201-206 (1990).
`22. Hartmann, H.A. et al. Science 251 , 942-944
`(1991).
`
`Breast cancer genes: how many,
`where and who are they?
`
`Department of
`Molecular and Cell
`Biology, University
`of California,
`Berkeley, California
`94720, USA
`
`Mary-Claire King
`
`Two papers in this issue of Nature
`Genetics add two pieces to the puzzle
`that will eventually reveal the genes
`responsible for inherited breast cancer
`and very likely breast cancer among
`women in the general population as
`well. One report on, page 128, suggests
`that the breast cancer gene BRCAJ on
`chromosome 17 q may act as a tumour
`suppressor 1
`: the other report on page
`132, demonstrates that a mutation in
`the androgen receptor gene on the X
`chromosome can cause male breast
`cancer, as well as androgen
`insufficiency2
`• How do these quite
`distinct findings fit into the evolving
`story of breast cancer genetics?
`The great majority ofbreast cancers
`are due solely to acquired mutations.
`Only about 5% of breast cancer
`patients have inherited mutations
`leading to the disease, although this
`fraction is much higher among
`younger patients (perhaps 40% of
`breast cancer diagnosed before age 30
`involves inherited alterations)3.
`However, these inherited mutations
`may alter the same genes that are the
`sites of acquired mutations and
`
`hence be critical to breast cancer
`development in the population as a
`whole. Furthermore, the inherited
`mutations clearly exist for decades in
`a woman's life before the tumours
`appear, so are early events in the
`tumorigenesis. The
`inherited
`mutations are also worth pursuing
`for their own sake. Inherited breast
`cancer is a common genetic disease:
`5% of a disease affecting one in ten
`women over the life span means that
`roughly one in 200 women will
`develop breast cancer by reason of
`inherited susceptibilty. Therefore, as
`an inherited trait, breast cancer is one
`of the most common genetic diseases
`in the industrialized world.
`Not all inherited breast cancer is
`due to alterations of the same gene.
`By far the largest proportion of
`inherited breast cancer has been
`attributed to the still-uncloned gene
`BRCAJ, on chromosome 17q21(refs
`4,5). Perhaps 60% of families with at
`least three breast cancer patients, and
`nearly all families with multiple cases
`of both breast and ovarian cancer,
`trace susceptibility to BRCAJ(ref. 6).
`
`nature genetics
`
`volume 2 october 1992
`
`(Many of the remarmng 40% of
`families may represent coincidental
`occurrence of breast cancer in
`relatives, rather than inherited
`predisposition, given the very high
`rate of purely "acquired" breast
`cancer.) Gene mapping in families
`with breast cancer, and often ovarian
`cancer, has narrowed the region that
`must contain BRCAJ to a few
`centiMorgans (eM), flanked by the
`markers THRAJ and Mfd188
`(D 175250 J7'8
`• Genes thereby excluded
`by position from being BRCA1
`include HER2/neu/ erbb 2, the thyroid
`hormone receptor, WNT3, HOX2,
`prohibitin9
`, collagen I (A1) and
`NM23. Perhaps the most biologically
`plausible candidate gene within the
`linked interval is that for 17-~
`hydroxysteroid dehydrogenase,
`although persumably another
`hundred or genes lie in this region as
`well. The use of more than 20 ordered
`polymorphic markers in this small
`region and multiple families with
`informative recombinants, should
`permit BRCAJ to be localized to
`roughly 1 eM by gene mapping. It will
`
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`news & views
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`be tedious, but straightforward, to
`identify all the transcripts in the
`smallest definable linked interval, and
`to compare sequences of these genes
`among susceptible versus not
`susceptible relatives.
`Analysis of tumours of breast and
`ovarian cancer patients in families
`with disease linked to 17q suggests
`that BRCAl may be a tumour
`suppressor gene. The evidence is the
`observation that the tumours from
`patients who have inherited mutant
`BRCAl have often lost all or a portion
`of chromosome 17q. When deletions
`in tumours are observed, the lost 17q
`chromosome is
`invariably the
`chromosome with the normal
`(nonmutant) allele of BRCAl. This
`suggests either that BRCAl is a
`tumour suppressor, so that the normal
`allele must be lost or altered for
`tumour development; or alternatively
`that BRCAl
`is a dominant
`predisposing gene very near a still(cid:173)
`unknown tumour suppressor, with
`acquired alterations in the tumour
`suppressor associated with selection
`for retention of the mutant BRCAl in
`the tumour. Once BRCAl is identi(cid:173)
`fied, these two hypotheses can be easily
`distinguished.
`Other genes responsible for
`inherited breast cancer have been
`identified. As demonstrated by
`Wooster et aF, a point mutation in
`the androgen receptor gene on the X
`chromosome can lead to breast cancer
`and androgen insufficiency among
`males. In other families, susceptibility
`to male breast cancer appears to be
`transmitted from father to son and
`
`appears with breast cancer in related
`females 4• Breast cancer in atleast some
`of these families is not linked to either
`X or 17 q, indicating the existence of
`at least one other gene associated with
`breast cancer in males.
`The first gene identified for
`inherited breast cancer was p53, which
`is responsible for the Li-Fraumeni
`• In addition to breast
`syndrome 10
`cancer among adult women, these
`families have extremely high rates of
`brain
`tumours, sarcoma and
`adrenocortical cancers among
`children with mutant p53. Other
`cancers also appear among adults.
`About 1 o/o of women diagnosed with
`breast cancer before age 30 have
`germline mutations in p53.
`In many families with multiple
`patients with breast cancer, the disease
`is clearly not linked to any of these
`genes. Breast cancer in most families
`has been diagnosed at older ages, so
`many cases may be due entirely to
`acquired mutations, rather than
`inherited susceptibility 11
`• However,
`there are certainly families in which
`breast cancer is attributable to
`inherited alterations at as-yet(cid:173)
`unidentified loci. Cancers of the
`colon, prostate, uterus or thyroid
`appear at high frequency in some of
`these families, as occasionally does
`breast cancer in males. Searches for
`the genes critical to inherited
`susceptibility in these families focus
`now on chromosomal regions
`frequently deleted in the tumours
`observed 12•
`Identification of the genes for
`inherited breast cancer will only be
`
`the end of the beginning of the story:
`attention will turn to biology and
`epidemiology. What are the normal
`and mutant products of the genes?
`What are the different mutations at
`each locus and how do they differ in
`site and severity? What proportion of
`breast and ovarian cancers in the
`general population are attributable
`to acquired mutations at these loci?
`How do alterations at the heritable
`sites interact with acquired alterations
`of HER2/neu/erbb-2, p53, cyclin D1,
`NM23 and so on? Clinically, it will be
`important to determine which
`compounds are most effective against
`each tumour genotype. Perhaps most
`usefully, identifying mutations that
`occur early in tumorigenesis should
`enable the development of molecular
`approaches
`for much earlier
`diagnosis, when tumour size can be
`measured in centiMorgans rather
`0
`than centimetres.
`
`References
`1. Smith, S.A., Easton, D.F., Evans, D.G.R. &
`Ponder, B.A.J. Nature Genet. 2,128--131 (1992).
`2. Wooster, R. eta/. Nature Genet. 2, 132-134
`(1992).
`3. Claus, E. B., Risch, N. & Thompson, W.D.Am. J.
`hum. Genet. 48,232-242 (1991).
`4. Haii,J.M.eta/.Science250, 1684-1689(1990).
`5. Narod, S.A. eta/. Lancet338, 82-83 (1991).
`6. Easton, D.M., Bishop, D.T., Ford, D. &Crockford,
`G.P. Am. J. hum. Genet. (in the press).
`7. Hall, J.M. eta/. Am. J. hum. Genet. 50 1235-
`1242 (1 992).
`8. Bowcock, A.M. eta/. Am. J. hum. Genet. (in the
`press).
`9. Sato, T.etal. Cancer Res. 52, 1643-1646(1992).
`10. Malkin, D. Science 230, 1233-1238 (1990).
`11. Margaritte, P., Bonaiti-Pellie, C., ~~g. M-C. &
`Clerget-Darpoux, F. Am. J. hum. Genet. 50
`1231-1234 (1992).
`12. Sato, T., Akiyama, f., Sakamoto, G., Kasumi, F.
`& Nakamura, Y. Cancer Res. 51 5794-5799
`(1991).
`
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`GeneDX 1027, pg. 4
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