Published in:
Open Access 01-12-2004 | Research article
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
Published in: BMC Neurology | Issue 1/2004
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Background
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.
Methods
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 GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA).
Results
A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals.
Conclusions
This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 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 GAD1 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.
Table 4
GAD1 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. *Nucleotide positions were not provided by Maestrini et al. [47].
Source | SNP position in mRNA, from the translational start site (bp) | Gene position of SNP(bp) | Amino acid change |
|---|---|---|---|
(A)Lappalainen et al. (2002) | A(-478)Del | Exon 0 (73) |
No substitution
|
(B)Lappalainen et al. (2002) | G(-147)A | Exon 0 (404) |
No substitution
|
(C)Lappalainen et al. (2002) | A(-39)C | Exon 1 (25) |
No substitution
|
(D)Spastic CP patients family B | G(36)C | Exon 1 (97) |
Ser(12)Cys
|
(E)NCBI collated resource | G(48)C | Exon 1 (104) |
Pro(17)Ala
|
(F)Control samples & family A NCBI collated resource | T(110)C | Exon 2 (29) |
No substitution
|
(G)Kure et al. (1998) | T(315)C | Exon 4 (14) |
No substitution
|
(H)Bu and Tobin (1994) Kure et al. (1998) | A(407)G | Exon 4 (105) |
No substitution
|
(I)Maestrini et al. (2002)* | G/C | Intron 4 |
No substitution
|
(J)NCBI collated resource | C(696)T | Exon 6 (56) |
No substitution
|
(K)Lappalainen et al. (2002) | T/Del | Intron 7 (35) |
No substitution
|
(L)In control samples Lappalainen et al. (2002) | T/C | Intron 8 (185) |
No substitution
|
(M)Maestrini et al. (2002)* | C/T | Intron 9 |
No substitution
|