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Molecular mechanisms of inherited startle syndromes
Molecular mechanisms of inherited startle syndromes ‘0 L._ 4 \5- Sundran +C+Q
Rajendra and Peter R. Schofield
Inherited neurological
disorders involving an exaggerated startle response to unexpected
sensory stimuli have been identified in mice, cows, dogs, horses and humans. Recent studies of the molecular pathology of a number of these startle syndromes have revealed that they are caused by defects In the inhibitory glycinergic pathways that mediate reciprocal and recurrent inhibition in the splnal cord. These defects arise from various mutations of the receptor for glycine, which either Smpalrits sensitivity to agonistsor reduce its expression in vlvo. The emergent models of the molecular mechanisms that underlie startle disorders illustrate how diverse mutations can converge physiologicallyto produce a common pheno-
VPe* Tro~ds Ncrrroscl. (1995) 18, 80-82
S of arms
TARTLE IS A stereotyplc facial grimacing,
response that Involves the hunching of shoulders, flexure
and clenching of flsts In response to an unexpected stimulus. Pathological dlsorders of the startle response were first described In 1878 in a community of French-Canadian lumberjacks’. While automatic speech and forced obedience were notable features of this report, startle syndromes are typlfled mole commonly by muscular rlgidlty (hypertonia) subsequent to a sudden noise or touch, resulting In an uncontrolled fall’-“. lnherlted startle syndromes have been defined In humans as startle dlsease (hyperekplexla or Kok’s diseaseJ2*,‘,in mice In the mutant lines spnswrlid and spnstic’, and In cows”, do8s’ and horse9 as myoclonus. Explanations of startle syndromes have focused on imp red braln reticular structures’, 0~ excitatory or inhibitory neurotransmitter systems “‘*“. However, recent studies of the molecular pathology of a number of startle syndromes have confirmed that defects in Inhibitory glyclnergk pathways are Tesponsible’“-.I“.
subunltsz,‘. Both types of subunits are related structurally, sharing 35% sequence identity, and consist of a large N-termlnus extracellular domain with four putatlve membrane-spannlng segments which form an Integral Cl- channel (Fig. 1)‘“. When expressed In Xerrop~rs oocytes or cultured mammallan cells, recombinant glycine-receptor or1 subunits (but not p subunits) readily form functional homomerlc rcceptars with properties similar to those of spinal-cord glycine receptors2fi~27.Glyclne and strychnine blnd exclusively to the (Ysubunits of the receptor2’J~2”-z’. The p subunits appear to promote and stabilize assembly of glyclne receptorP2’. Impaired receptor function in familial startle disease
Genetic linkage analysis of human startle-disease pedigrees mapped this disorder to human chromosome Sq32 (Ref. 281, an area which contains the genes for several neurotransmitter receptors, IncludIng the glycine ~eceptor2”*ay.A subsequent study demonstrated the presence of missense mutations In Glycine-mediated neurotranrmission the glycine receptor al-subunit gene’“. These muGlyclne is the major inhibitory neurotransmitter tations replace a positively charged arginine residue In the spinal cord. The binding of glyclne to its post- at position 271 with an uncharged residue, either synaptic receptor underlies the reciprocal and recur- leucine or glutamlne (Fig. 1). When measured using rent inhibition that is essential for the normal func- patch-clamp techniques, homomerlc al-subunlt g!ytioning of spinal cord reflexes, muscle tone and the clne receptors that contain startle-disease mutations proccsslng of afferent signals”. The actions of show ZJO- to 410-fold decreases In the sensitivities glycine and the glycine-receptor agonists, P-alanine of glycine-activated currents, and reduced channel and taurine, are antagonized rompetitlvely by conductances”s3”, with no accompanying reduction strychnine. Sub-convulsive doses of this plant alka- in the sensitivity to strychnine or In the number of loid produce an acute responsiveness to sensory receptor molecules expressed on the cell surface’“,“‘J”. stlmull, whereas acute poisoning results in severe Interestingly, these mutations also transform the generalized hypertonia’“. Both symptoms bear a glyclne-receptor agonists, P-alanine and taurine, Into remarkable similarity to those of human and animal competitive antagonlsts”‘. These findings, coupled startle syndromes. with the location of the arginine residue at the Glycine-receptor agonists and antagonists bind to border of the receptor’s ion channel”“, suggest that the glycine receptor”‘, a member of the ligand .gated this residue Is a crucial element of the mechanism ion-channel superfamily”‘,2z that mediates fast that transduces binding of agonist into channel synaptic transmission in the nervous system. The opening”‘,‘“. The startle-disease mutations have thus glycine receptor is a pentameric complex which, in identified a novel functional site in the glycine adults, comprises three cul subunits and two p receptor.
$4.Ra@adraand P. Sd~otldd - Inheritedstank syndranws
PEESPECTIVES OS DISEASE
Murine mutations producing startle syndromes The stactledisease phenotype heats a striking resemblance to that of the autosomal recessive mucine mutations, spasmodic and spastic. In response to unexpected stimuli, spasmodic and spastic homozygotes exhibit an exaggerated startle cesponse, which is characterized by muscle tremor and hypectonia, falling and impaired cightic@. The recent appearance of evidence linking these autosomal recessive conditions to defects in subunits of glycine receptors is, therefore, not unexpected. In the case of spasmodic, a missense mutation in the alsubunit gene has been identified. This mutation results in the replacement of an alaninc with a sccine residue at position 52, neat the subunit’s extcacellular N-terminus (Fig. 1)‘s*‘6.The spasmodic mutation, when expressed in recombinant al-subunit glycine receptors, produces a 60% reduction in sensitivity of the glycine-activated .cuccent’sJ*. In contrast to both startle disease and spusmo&, a defect In the glyclne-receptor @-subunitgene r!ildetlies spastic“. This defect arises from the intconic inscction of a LINE-1transposable element, a ubiquitous repetitive sequence motif that is usually found in Inactivepseudogene-likesequences, which ccsults in reduced expression levels” or aberrant splicing of B-subunit mRNA”, or both. Whilst spnsffc glycine receptors in the spinal cord function normally, receptor numbers ace ceduced dramatically in comparison to receptor levels observed in wild-type animals”~“‘.This decrease correlates with a major reduction in the levels of @-subunit mRNA in the spinal cord and brain “, indicating that the spastic mutation prevents the expression of the g-subunit mRNAand, thus, the efficient assembly of the ceceptoc’7*2”27. Reducer! expression of glycine receptors in the spinal cord is also characteristic of the bovine and equine forms of myoclonus”~*.However, it is not yet known if these startle syndromes ace caused by a similar P-subunit defect. The spasmodic and spastic phenotypes do not manifest until two weeks after birth. This suppocts the suggestion that neonatal glycine ceceptocs ace composed solely of a2 subunits, and that, normally, these pharmacologically distinct homomecic glycine receptors ace replaced rapidly after birth with the adult al&subunit hetecomec in the spinal cord”“. Mice with an allelic variant of spnsrntiic, oscillator’“, ace also phenotypically nocmal until two weeks after birth, but die by three weeks of age. The molr:ulac bask, of oscillator will therefore be of considerable interest. With the exception of oscillator, all startle syndromes described above are rarely letha124, yet all appear to severely impair glycine-receptor fimction or expression. For startle disease, the dramatic ceductions in agonist sensitivity obsecved in cecombinant glycine receptors might be smaller b viw as a result of the autosomal dominant nature of the disease""J2, which would result in the co-expression of normal and mutant al subunits in glycine receptors and, thus, the retention of some glycinecgic tone in the spinal cord. Indeed, recombinant glycine receptors co-expressing normal and mutant subunits display only a 90% reduction in the sensitivily of glycine-activated currents IJ. Such an explanation is clearly not applicable to the autosomal cecessive
F@ 1. ~~~eMtf0~ Of tk gf$*rU@r al subunit. Spherec we amino acid resfdues with single letter code. Stortkyndmme mutatiovsaffectingthe shine s~sftivity of the grvcinereccptcr @Ml Wur ot residue SZ (Orcmine to wine) in the murine mutation, spasmodic,tmd residue271(ayinine to eitherkxine orglutamine]in fomiliolstartledisease. Both of these mutations are distantto the receptor’sputativeg&c&binding site, whichis formedby rp~idues 159-W andZOO(Refs 24 o.?dZS).
mucine mutatious that display reduced function of glycine ceceptocs if1 viw. This suggests that other inhibitory neucotcansmittec systems might compensate for the glycine ceceptoc-mediated deficits that arise from startle syndromes. Startle syndromes can be treated effectively with phenobacbitone or clonazepam’*“. indicating that inhibitory GABAecgic pathways remain intact. GABAecgictom? appears to be enhanced in some startle syndcomes, as increased numbers of GABA-bindingsites ace present in the spinal cord and brain of myori0nir cattle”‘.
syasric mice”
and
Concluding remarks
Investigations of the molecular basis of startle syndromes have identified unexpected determinants of the function of glydne receptors. This information has also provided insighti into the develop ment of glycinecgic pathways in the spinal cord. At a more general level, these studies demonstcate how divecse mutations can converge physiolagically (Fig. 2). The startle syndromes affecting glycinemediated neucotcansmission desccibed to date can
be grouped into two distinct classes: those that 77X.5 Vcrl. 18.sa.2. 1ws
81
S. Rajsndra and P. Schofield - Inheritedstartlesyndromes
PERSPECTIVES GN DISEASE
Startle disease R271 L, R271Q
Reduced glycine-receptor sensitivity
Reduced glycinerglc inhibition in the spinal cord
spasmodic A52S
Reduced glycine-receptor expression
spastic lntronlc LINE-1
transposable element
Fig. 2. The molecukur mechanisms of various startle disorders converge physlolog/ca/ly.
Mlssense mutations in the gene encudlng the
glycine-receptoral subunit ore responsible for the reduced agonist sensitivity of the receptor that results from fornlllol startle dlseose and the murine mutation spasmodic. In murlne mutotlon spastic, an htmnic insertion of a LINE-7 bunsposable element into the glyclne-receptor p-subunit gene results in exon skipping and reduced receptor expresslon In the splnol cord. PhenotypkMy, o/l three disorders diminish glycinegic inhibltion In the splnol cord, resulting in hypertonia and on excessive startle response. 15 Ryan, S.G. et RI. (1994) NatureGenet.7, 131-135
impair
the function of glycine receptors by reducing the receptor’s sensitivity to agonists (startle disease and spasmo&), and those that prevent or diminish expression of glycine receptors (spastic and bovine myoclonus). l3oth mechanisms converge to diminish glycinergic tone in the nervous system, thereby generating symptoms that are characteristic of these startle syndromes. The common phenotype of other startle syndromes, such as lutak in the Malay archipelaga’
and
suggests
that
the
various
these
forms
disorders
of
might
16 Saul, B. et al. (1994) FEBSLelt. 350,71-76 17 Kingsmore, S.F. et al. (1994) NatureGent?. 7,136-141 18 Mulhardt, C. et al. (1994) Nerttwn13,1003-1015 19 GoodmarbGilman, A. et al. (1991) Goo&~an and Gilman’s: The N~nrmacologk~l B&s of Thempeutlcs (8th edn), p. 1632, Macmillan 20 Grenningloh, G. et al. (1987) N&we 328,21S-220 21 Schofield, P.R. et al. (1987) Nature 328,221-227 22 Devlllers-Thlery, A. et al. (1994) 1. Membr. Mol. 136,97-112 23 Langorch, D., Thomas, L. and Ret& H, (1988) Proc. Nat/
Acnd. Sd. USA 85,7394-7398 24 Vandenberg, RJ., Handford, C.A. and Schofield, P.R. (1992) Neuron 9,491-496 25 Schmieden, V., Kuhse, J. and Betz, Ii. (1993) Science 262, 256-258 26 Kuhse, J. et al. (1993) Neumn11,1049-1096
myoclonuP, also
fall into
one of these two classes. Note
added in proof
27 Grennlngloh, G. et al. (1990) Newon 4,963-970
Reeset al.35 have recently identified o recessive missense mutation (Asn for f/e ot position 244) that is located at the intracellular boundary of the first tronsmembmne domoin.
Selected rcfercnces
1 Beard, G.M. (1878) I. NW. Ment. Dls. 5,526 2 Suhren, O., BN~II. G.W. and Tuynman, J.A. (1966) I. Newof. sci. 3. 577-605 R And&mann, F. and Andermann, E. (198R) Rmin Drv, 4. 213-222 4 Lane, F.W. et nl. (1987) \. Hered. 78.353-356 5 Chai, C.K. (1961) 1. fIcrcci.S&241- !43 6 Gundlach, A.L. et al. (1988) Sciw.. 241. 1837-1810 7 Holland, J.M. et al. (1970) Am. 1. P&d. 58, 509-530 8 Gundlach, A.L. et al. (1993) Emit1Rcs. 628, 263-270 9 Snodgrass, S.R. (199i1, k\SEll I. 4,27X--2788. 10iiuckwlter, hi.S. et crE.(1193) Genomlcs 17, 27&286
11 12 13 14
White, W.F. and Helter, A.H. (1982) Nnhtre298,6SS-657 Shlan8, R. et al. (1993) NnhtrcGerrct.S, 351-358 Raiendra, S. et al. (1994) I. Biol. Chem. 269, 18739-18742 Lan8oosch,D. et al. (1994) EMBOI. 13,4223-4228
TIM Vol. 18, No. 2. 1995
.
28 Ryan, S.G. et al. (1992) Am. I. Hum. Geuet. S1,1334-1343 29 Baker, E., Sutherland, G.R. and Schofield, P.R. (1994) Gerlomics22,491-493 30 Raicndn, S. et rrl. Neumrt (In press) 31 White, W.F. (1985) Bmin Res. 329, l-6 32 Becker, C-M. et al. (1992) Ncurou 8,283-289 33 Cook, S.A. (1993, MorrscGcnonte91, 117 34 Lummis, S.C. et al. (1990) I. Neumchem. SS,421-426 35 Rees, M-1. et al. Iften. Mol. Genet. (in press)
I Tiwds in Neumsciences Articles In TINS are usually commissioned by the Miter. In contultatlon with the Edltorial Board. All articles are subject to peer and editorial review and might be rejected: commissioning does not guarantee publication. -l
1
Rajendra and Peter R. Schofield
Inherited neurological
disorders involving an exaggerated startle response to unexpected
sensory stimuli have been identified in mice, cows, dogs, horses and humans. Recent studies of the molecular pathology of a number of these startle syndromes have revealed that they are caused by defects In the inhibitory glycinergic pathways that mediate reciprocal and recurrent inhibition in the splnal cord. These defects arise from various mutations of the receptor for glycine, which either Smpalrits sensitivity to agonistsor reduce its expression in vlvo. The emergent models of the molecular mechanisms that underlie startle disorders illustrate how diverse mutations can converge physiologicallyto produce a common pheno-
VPe* Tro~ds Ncrrroscl. (1995) 18, 80-82
S of arms
TARTLE IS A stereotyplc facial grimacing,
response that Involves the hunching of shoulders, flexure
and clenching of flsts In response to an unexpected stimulus. Pathological dlsorders of the startle response were first described In 1878 in a community of French-Canadian lumberjacks’. While automatic speech and forced obedience were notable features of this report, startle syndromes are typlfled mole commonly by muscular rlgidlty (hypertonia) subsequent to a sudden noise or touch, resulting In an uncontrolled fall’-“. lnherlted startle syndromes have been defined In humans as startle dlsease (hyperekplexla or Kok’s diseaseJ2*,‘,in mice In the mutant lines spnswrlid and spnstic’, and In cows”, do8s’ and horse9 as myoclonus. Explanations of startle syndromes have focused on imp red braln reticular structures’, 0~ excitatory or inhibitory neurotransmitter systems “‘*“. However, recent studies of the molecular pathology of a number of startle syndromes have confirmed that defects in Inhibitory glyclnergk pathways are Tesponsible’“-.I“.
subunltsz,‘. Both types of subunits are related structurally, sharing 35% sequence identity, and consist of a large N-termlnus extracellular domain with four putatlve membrane-spannlng segments which form an Integral Cl- channel (Fig. 1)‘“. When expressed In Xerrop~rs oocytes or cultured mammallan cells, recombinant glycine-receptor or1 subunits (but not p subunits) readily form functional homomerlc rcceptars with properties similar to those of spinal-cord glycine receptors2fi~27.Glyclne and strychnine blnd exclusively to the (Ysubunits of the receptor2’J~2”-z’. The p subunits appear to promote and stabilize assembly of glyclne receptorP2’. Impaired receptor function in familial startle disease
Genetic linkage analysis of human startle-disease pedigrees mapped this disorder to human chromosome Sq32 (Ref. 281, an area which contains the genes for several neurotransmitter receptors, IncludIng the glycine ~eceptor2”*ay.A subsequent study demonstrated the presence of missense mutations In Glycine-mediated neurotranrmission the glycine receptor al-subunit gene’“. These muGlyclne is the major inhibitory neurotransmitter tations replace a positively charged arginine residue In the spinal cord. The binding of glyclne to its post- at position 271 with an uncharged residue, either synaptic receptor underlies the reciprocal and recur- leucine or glutamlne (Fig. 1). When measured using rent inhibition that is essential for the normal func- patch-clamp techniques, homomerlc al-subunlt g!ytioning of spinal cord reflexes, muscle tone and the clne receptors that contain startle-disease mutations proccsslng of afferent signals”. The actions of show ZJO- to 410-fold decreases In the sensitivities glycine and the glycine-receptor agonists, P-alanine of glycine-activated currents, and reduced channel and taurine, are antagonized rompetitlvely by conductances”s3”, with no accompanying reduction strychnine. Sub-convulsive doses of this plant alka- in the sensitivity to strychnine or In the number of loid produce an acute responsiveness to sensory receptor molecules expressed on the cell surface’“,“‘J”. stlmull, whereas acute poisoning results in severe Interestingly, these mutations also transform the generalized hypertonia’“. Both symptoms bear a glyclne-receptor agonists, P-alanine and taurine, Into remarkable similarity to those of human and animal competitive antagonlsts”‘. These findings, coupled startle syndromes. with the location of the arginine residue at the Glycine-receptor agonists and antagonists bind to border of the receptor’s ion channel”“, suggest that the glycine receptor”‘, a member of the ligand .gated this residue Is a crucial element of the mechanism ion-channel superfamily”‘,2z that mediates fast that transduces binding of agonist into channel synaptic transmission in the nervous system. The opening”‘,‘“. The startle-disease mutations have thus glycine receptor is a pentameric complex which, in identified a novel functional site in the glycine adults, comprises three cul subunits and two p receptor.
$4.Ra@adraand P. Sd~otldd - Inheritedstank syndranws
PEESPECTIVES OS DISEASE
Murine mutations producing startle syndromes The stactledisease phenotype heats a striking resemblance to that of the autosomal recessive mucine mutations, spasmodic and spastic. In response to unexpected stimuli, spasmodic and spastic homozygotes exhibit an exaggerated startle cesponse, which is characterized by muscle tremor and hypectonia, falling and impaired cightic@. The recent appearance of evidence linking these autosomal recessive conditions to defects in subunits of glycine receptors is, therefore, not unexpected. In the case of spasmodic, a missense mutation in the alsubunit gene has been identified. This mutation results in the replacement of an alaninc with a sccine residue at position 52, neat the subunit’s extcacellular N-terminus (Fig. 1)‘s*‘6.The spasmodic mutation, when expressed in recombinant al-subunit glycine receptors, produces a 60% reduction in sensitivity of the glycine-activated .cuccent’sJ*. In contrast to both startle disease and spusmo&, a defect In the glyclne-receptor @-subunitgene r!ildetlies spastic“. This defect arises from the intconic inscction of a LINE-1transposable element, a ubiquitous repetitive sequence motif that is usually found in Inactivepseudogene-likesequences, which ccsults in reduced expression levels” or aberrant splicing of B-subunit mRNA”, or both. Whilst spnsffc glycine receptors in the spinal cord function normally, receptor numbers ace ceduced dramatically in comparison to receptor levels observed in wild-type animals”~“‘.This decrease correlates with a major reduction in the levels of @-subunit mRNA in the spinal cord and brain “, indicating that the spastic mutation prevents the expression of the g-subunit mRNAand, thus, the efficient assembly of the ceceptoc’7*2”27. Reducer! expression of glycine receptors in the spinal cord is also characteristic of the bovine and equine forms of myoclonus”~*.However, it is not yet known if these startle syndromes ace caused by a similar P-subunit defect. The spasmodic and spastic phenotypes do not manifest until two weeks after birth. This suppocts the suggestion that neonatal glycine ceceptocs ace composed solely of a2 subunits, and that, normally, these pharmacologically distinct homomecic glycine receptors ace replaced rapidly after birth with the adult al&subunit hetecomec in the spinal cord”“. Mice with an allelic variant of spnsrntiic, oscillator’“, ace also phenotypically nocmal until two weeks after birth, but die by three weeks of age. The molr:ulac bask, of oscillator will therefore be of considerable interest. With the exception of oscillator, all startle syndromes described above are rarely letha124, yet all appear to severely impair glycine-receptor fimction or expression. For startle disease, the dramatic ceductions in agonist sensitivity obsecved in cecombinant glycine receptors might be smaller b viw as a result of the autosomal dominant nature of the disease""J2, which would result in the co-expression of normal and mutant al subunits in glycine receptors and, thus, the retention of some glycinecgic tone in the spinal cord. Indeed, recombinant glycine receptors co-expressing normal and mutant subunits display only a 90% reduction in the sensitivily of glycine-activated currents IJ. Such an explanation is clearly not applicable to the autosomal cecessive
F@ 1. ~~~eMtf0~ Of tk gf$*rU@r al subunit. Spherec we amino acid resfdues with single letter code. Stortkyndmme mutatiovsaffectingthe shine s~sftivity of the grvcinereccptcr @Ml Wur ot residue SZ (Orcmine to wine) in the murine mutation, spasmodic,tmd residue271(ayinine to eitherkxine orglutamine]in fomiliolstartledisease. Both of these mutations are distantto the receptor’sputativeg&c&binding site, whichis formedby rp~idues 159-W andZOO(Refs 24 o.?dZS).
mucine mutatious that display reduced function of glycine ceceptocs if1 viw. This suggests that other inhibitory neucotcansmittec systems might compensate for the glycine ceceptoc-mediated deficits that arise from startle syndromes. Startle syndromes can be treated effectively with phenobacbitone or clonazepam’*“. indicating that inhibitory GABAecgic pathways remain intact. GABAecgictom? appears to be enhanced in some startle syndcomes, as increased numbers of GABA-bindingsites ace present in the spinal cord and brain of myori0nir cattle”‘.
syasric mice”
and
Concluding remarks
Investigations of the molecular basis of startle syndromes have identified unexpected determinants of the function of glydne receptors. This information has also provided insighti into the develop ment of glycinecgic pathways in the spinal cord. At a more general level, these studies demonstcate how divecse mutations can converge physiolagically (Fig. 2). The startle syndromes affecting glycinemediated neucotcansmission desccibed to date can
be grouped into two distinct classes: those that 77X.5 Vcrl. 18.sa.2. 1ws
81
S. Rajsndra and P. Schofield - Inheritedstartlesyndromes
PERSPECTIVES GN DISEASE
Startle disease R271 L, R271Q
Reduced glycine-receptor sensitivity
Reduced glycinerglc inhibition in the spinal cord
spasmodic A52S
Reduced glycine-receptor expression
spastic lntronlc LINE-1
transposable element
Fig. 2. The molecukur mechanisms of various startle disorders converge physlolog/ca/ly.
Mlssense mutations in the gene encudlng the
glycine-receptoral subunit ore responsible for the reduced agonist sensitivity of the receptor that results from fornlllol startle dlseose and the murine mutation spasmodic. In murlne mutotlon spastic, an htmnic insertion of a LINE-7 bunsposable element into the glyclne-receptor p-subunit gene results in exon skipping and reduced receptor expresslon In the splnol cord. PhenotypkMy, o/l three disorders diminish glycinegic inhibltion In the splnol cord, resulting in hypertonia and on excessive startle response. 15 Ryan, S.G. et RI. (1994) NatureGenet.7, 131-135
impair
the function of glycine receptors by reducing the receptor’s sensitivity to agonists (startle disease and spasmo&), and those that prevent or diminish expression of glycine receptors (spastic and bovine myoclonus). l3oth mechanisms converge to diminish glycinergic tone in the nervous system, thereby generating symptoms that are characteristic of these startle syndromes. The common phenotype of other startle syndromes, such as lutak in the Malay archipelaga’
and
suggests
that
the
various
these
forms
disorders
of
might
16 Saul, B. et al. (1994) FEBSLelt. 350,71-76 17 Kingsmore, S.F. et al. (1994) NatureGent?. 7,136-141 18 Mulhardt, C. et al. (1994) Nerttwn13,1003-1015 19 GoodmarbGilman, A. et al. (1991) Goo&~an and Gilman’s: The N~nrmacologk~l B&s of Thempeutlcs (8th edn), p. 1632, Macmillan 20 Grenningloh, G. et al. (1987) N&we 328,21S-220 21 Schofield, P.R. et al. (1987) Nature 328,221-227 22 Devlllers-Thlery, A. et al. (1994) 1. Membr. Mol. 136,97-112 23 Langorch, D., Thomas, L. and Ret& H, (1988) Proc. Nat/
Acnd. Sd. USA 85,7394-7398 24 Vandenberg, RJ., Handford, C.A. and Schofield, P.R. (1992) Neuron 9,491-496 25 Schmieden, V., Kuhse, J. and Betz, Ii. (1993) Science 262, 256-258 26 Kuhse, J. et al. (1993) Neumn11,1049-1096
myoclonuP, also
fall into
one of these two classes. Note
added in proof
27 Grennlngloh, G. et al. (1990) Newon 4,963-970
Reeset al.35 have recently identified o recessive missense mutation (Asn for f/e ot position 244) that is located at the intracellular boundary of the first tronsmembmne domoin.
Selected rcfercnces
1 Beard, G.M. (1878) I. NW. Ment. Dls. 5,526 2 Suhren, O., BN~II. G.W. and Tuynman, J.A. (1966) I. Newof. sci. 3. 577-605 R And&mann, F. and Andermann, E. (198R) Rmin Drv, 4. 213-222 4 Lane, F.W. et nl. (1987) \. Hered. 78.353-356 5 Chai, C.K. (1961) 1. fIcrcci.S&241- !43 6 Gundlach, A.L. et al. (1988) Sciw.. 241. 1837-1810 7 Holland, J.M. et al. (1970) Am. 1. P&d. 58, 509-530 8 Gundlach, A.L. et al. (1993) Emit1Rcs. 628, 263-270 9 Snodgrass, S.R. (199i1, k\SEll I. 4,27X--2788. 10iiuckwlter, hi.S. et crE.(1193) Genomlcs 17, 27&286
11 12 13 14
White, W.F. and Helter, A.H. (1982) Nnhtre298,6SS-657 Shlan8, R. et al. (1993) NnhtrcGerrct.S, 351-358 Raiendra, S. et al. (1994) I. Biol. Chem. 269, 18739-18742 Lan8oosch,D. et al. (1994) EMBOI. 13,4223-4228
TIM Vol. 18, No. 2. 1995
.
28 Ryan, S.G. et al. (1992) Am. I. Hum. Geuet. S1,1334-1343 29 Baker, E., Sutherland, G.R. and Schofield, P.R. (1994) Gerlomics22,491-493 30 Raicndn, S. et rrl. Neumrt (In press) 31 White, W.F. (1985) Bmin Res. 329, l-6 32 Becker, C-M. et al. (1992) Ncurou 8,283-289 33 Cook, S.A. (1993, MorrscGcnonte91, 117 34 Lummis, S.C. et al. (1990) I. Neumchem. SS,421-426 35 Rees, M-1. et al. Iften. Mol. Genet. (in press)
I Tiwds in Neumsciences Articles In TINS are usually commissioned by the Miter. In contultatlon with the Edltorial Board. All articles are subject to peer and editorial review and might be rejected: commissioning does not guarantee publication. -l
1