Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders
<p>Abstract</p> <p>Background</p> <p>Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which sh...
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| Format: | Article |
| Language: | English |
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BMC
2004-11-01
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| Series: | BMC Neurology |
| Online Access: | http://www.biomedcentral.com/1471-2377/4/20 |
| _version_ | 1818757357178454016 |
|---|---|
| author | Woods C Geoffrey Maher Eamonn R Mitchell Simon Achuthan Rajgopal Leek Jack P Carr Ian M Lynex Clare N Bonthon David T Markham Alex F |
| author_facet | Woods C Geoffrey Maher Eamonn R Mitchell Simon Achuthan Rajgopal Leek Jack P Carr Ian M Lynex Clare N Bonthon David T Markham Alex F |
| author_sort | Woods C Geoffrey |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families.</p> <p>Methods</p> <p>Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene <it>GAD1</it>, which encodes a glutamate decarboxylase isoform (GAD<sub>67</sub>), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA).</p> <p>Results</p> <p>A novel amino acid mis-sense mutation in GAD<sub>67 </sub>was detected, which segregated with CP in affected individuals.</p> <p>Conclusions</p> <p>This result is interesting because auto-antibodies to GAD<sub>67 </sub>and the more widely studied GAD<sub>65 </sub>homologue encoded by the <it>GAD2 </it>gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the <it>GAD1 </it>sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts.</p> <tbl id="T4"> <title> <p>Table 4</p> </title> <caption> <p><it>GAD1</it> single nucleotide substitutions detected on mutation analysis and occurring in sequences submitted to NCBI SNP database and in the literature. This is not a definitive list, but includes those described at the time of the mutational analysis. *<it>Nucleotide positions were not provided by Maestrini et al</it>. [47].</p> </caption> <tblbdy cols="4"> <r> <c ca="center"> <p><b>Source</b></p> </c> <c ca="center"> <p><b>SNP position in mRNA, from the translational start site (bp)</b></p> </c> <c ca="center"> <p><b>Gene position of SNP(bp)</b></p> </c> <c ca="center"> <p><b>Amino acid change</b></p> </c> </r> <r> <c cspan="4"> <hr/> </c> </r> <r> <c ca="center"> <p>(A)Lappalainen <it>et al</it>. (2002)</p> </c> <c ca="center"> <p>A(-478)Del</p> </c> <c ca="center"> <p>Exon 0 (73)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(B)Lappalainen <it>et al</it>. (2002)</p> </c> <c ca="center"> <p>G(-147)A</p> </c> <c ca="center"> <p>Exon 0 (404)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(C)Lappalainen <it>et al</it>. (2002)</p> </c> <c ca="center"> <p>A(-39)C</p> </c> <c ca="center"> <p>Exon 1 (25)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(D)Spastic CP patients family B</p> </c> <c ca="center"> <p>G(36)C</p> </c> <c ca="center"> <p>Exon 1 (97)</p> </c> <c ca="center"> <p><it>Ser(12)Cys</it></p> </c> </r> <r> <c ca="center"> <p>(E)NCBI collated resource</p> </c> <c ca="center"> <p>G(48)C</p> </c> <c ca="center"> <p>Exon 1 (104)</p> </c> <c ca="center"> <p><it>Pro(17)Ala</it></p> </c> </r> <r> <c ca="center"> <p>(F)Control samples & family A NCBI collated resource</p> </c> <c ca="center"> <p>T(110)C</p> </c> <c ca="center"> <p>Exon 2 (29)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(G)Kure <it>et al</it>. (1998)</p> </c> <c ca="center"> <p>T(315)C</p> </c> <c ca="center"> <p>Exon 4 (14)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(H)Bu and Tobin (1994) Kure <it>et al</it>. (1998)</p> </c> <c ca="center"> <p>A(407)G</p> </c> <c ca="center"> <p>Exon 4 (105)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(I)Maestrini <it>et al</it>. (2002)*</p> </c> <c ca="center"> <p>G/C</p> </c> <c ca="center"> <p>Intron 4</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(J)NCBI collated resource</p> </c> <c ca="center"> <p>C(696)T</p> </c> <c ca="center"> <p>Exon 6 (56)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(K)Lappalainen <it>et al</it>. (2002)</p> </c> <c ca="center"> <p>T/Del</p> </c> <c ca="center"> <p>Intron 7 (35)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(L)In control samples Lappalainen <it>et al</it>. (2002)</p> </c> <c ca="center"> <p>T/C</p> </c> <c ca="center"> <p>Intron 8 (185)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(M)Maestrini <it>et al</it>. (2002)*</p> </c> <c ca="center"> <p>C/T</p> </c> <c ca="center"> <p>Intron 9</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> </tblbdy> </tbl> |
| first_indexed | 2024-12-18T06:09:39Z |
| format | Article |
| id | doaj.art-a7ab543ab8d94151b1a8afd1cca45ed8 |
| institution | Directory Open Access Journal |
| issn | 1471-2377 |
| language | English |
| last_indexed | 2024-12-18T06:09:39Z |
| publishDate | 2004-11-01 |
| publisher | BMC |
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| series | BMC Neurology |
| spelling | doaj.art-a7ab543ab8d94151b1a8afd1cca45ed82022-12-21T21:18:27ZengBMCBMC Neurology1471-23772004-11-01412010.1186/1471-2377-4-20Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disordersWoods C GeoffreyMaher Eamonn RMitchell SimonAchuthan RajgopalLeek Jack PCarr Ian MLynex Clare NBonthon David TMarkham Alex F<p>Abstract</p> <p>Background</p> <p>Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families.</p> <p>Methods</p> <p>Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene <it>GAD1</it>, which encodes a glutamate decarboxylase isoform (GAD<sub>67</sub>), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA).</p> <p>Results</p> <p>A novel amino acid mis-sense mutation in GAD<sub>67 </sub>was detected, which segregated with CP in affected individuals.</p> <p>Conclusions</p> <p>This result is interesting because auto-antibodies to GAD<sub>67 </sub>and the more widely studied GAD<sub>65 </sub>homologue encoded by the <it>GAD2 </it>gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the <it>GAD1 </it>sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts.</p> <tbl id="T4"> <title> <p>Table 4</p> </title> <caption> <p><it>GAD1</it> single nucleotide substitutions detected on mutation analysis and occurring in sequences submitted to NCBI SNP database and in the literature. This is not a definitive list, but includes those described at the time of the mutational analysis. *<it>Nucleotide positions were not provided by Maestrini et al</it>. [47].</p> </caption> <tblbdy cols="4"> <r> <c ca="center"> <p><b>Source</b></p> </c> <c ca="center"> <p><b>SNP position in mRNA, from the translational start site (bp)</b></p> </c> <c ca="center"> <p><b>Gene position of SNP(bp)</b></p> </c> <c ca="center"> <p><b>Amino acid change</b></p> </c> </r> <r> <c cspan="4"> <hr/> </c> </r> <r> <c ca="center"> <p>(A)Lappalainen <it>et al</it>. (2002)</p> </c> <c ca="center"> <p>A(-478)Del</p> </c> <c ca="center"> <p>Exon 0 (73)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(B)Lappalainen <it>et al</it>. (2002)</p> </c> <c ca="center"> <p>G(-147)A</p> </c> <c ca="center"> <p>Exon 0 (404)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(C)Lappalainen <it>et al</it>. (2002)</p> </c> <c ca="center"> <p>A(-39)C</p> </c> <c ca="center"> <p>Exon 1 (25)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(D)Spastic CP patients family B</p> </c> <c ca="center"> <p>G(36)C</p> </c> <c ca="center"> <p>Exon 1 (97)</p> </c> <c ca="center"> <p><it>Ser(12)Cys</it></p> </c> </r> <r> <c ca="center"> <p>(E)NCBI collated resource</p> </c> <c ca="center"> <p>G(48)C</p> </c> <c ca="center"> <p>Exon 1 (104)</p> </c> <c ca="center"> <p><it>Pro(17)Ala</it></p> </c> </r> <r> <c ca="center"> <p>(F)Control samples & family A NCBI collated resource</p> </c> <c ca="center"> <p>T(110)C</p> </c> <c ca="center"> <p>Exon 2 (29)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(G)Kure <it>et al</it>. (1998)</p> </c> <c ca="center"> <p>T(315)C</p> </c> <c ca="center"> <p>Exon 4 (14)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(H)Bu and Tobin (1994) Kure <it>et al</it>. (1998)</p> </c> <c ca="center"> <p>A(407)G</p> </c> <c ca="center"> <p>Exon 4 (105)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(I)Maestrini <it>et al</it>. (2002)*</p> </c> <c ca="center"> <p>G/C</p> </c> <c ca="center"> <p>Intron 4</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(J)NCBI collated resource</p> </c> <c ca="center"> <p>C(696)T</p> </c> <c ca="center"> <p>Exon 6 (56)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(K)Lappalainen <it>et al</it>. (2002)</p> </c> <c ca="center"> <p>T/Del</p> </c> <c ca="center"> <p>Intron 7 (35)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(L)In control samples Lappalainen <it>et al</it>. (2002)</p> </c> <c ca="center"> <p>T/C</p> </c> <c ca="center"> <p>Intron 8 (185)</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> <r> <c ca="center"> <p>(M)Maestrini <it>et al</it>. (2002)*</p> </c> <c ca="center"> <p>C/T</p> </c> <c ca="center"> <p>Intron 9</p> </c> <c ca="center"> <p><it>No substitution</it></p> </c> </r> </tblbdy> </tbl>http://www.biomedcentral.com/1471-2377/4/20 |
| spellingShingle | Woods C Geoffrey Maher Eamonn R Mitchell Simon Achuthan Rajgopal Leek Jack P Carr Ian M Lynex Clare N Bonthon David T Markham Alex F Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders BMC Neurology |
| title | Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders |
| title_full | Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders |
| title_fullStr | Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders |
| title_full_unstemmed | Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders |
| title_short | Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders |
| title_sort | homozygosity for a missense mutation in the 67 kda isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy parallels with stiff person syndrome and other movement disorders |
| url | http://www.biomedcentral.com/1471-2377/4/20 |
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