Re: SLC25A12 gene assiciated with autism - , your comments ?

May 1, 2004

Jay: Interesting but again with no (as yet) clinical implication. I do not

agree with their premise that it is largely genetic, but an interplay between

genetic factors and triggers in the form of toxic insults to the fetus or

infant. The prevailing notion that genes are cast in stone has been happily

knocked off its base with the recent studies showing environmental (nutrition,

toxins, etc) influences on genetic expression via the methylation process. Dr.

JM SLC25A12 gene assiciated with autism - , your

comments ?

Linkage and Association of the Mitochondrial Aspartate/Glutamate r

SLC25A12 Gene With Autism Nicolas Ramoz, Ph.D., G. Reichert, B.Sc.,

J. , Ph.D., M. Silverman, Ph.D., Irina N. Bespalova,

Ph.D., L. , M.D., and ph D. Buxbaum, Ph.D.

OBJECTIVE: Autism/autistic disorder (MIM number 209850) is a complex,

largely genetic psychiatric disorder. The authors recently mapped a

susceptibility locus for autism to chromosome region 2q24-q33 (MIM number

606053). In the present study, genes across the 2q24-q33 interval were analyzed

to identify an autism susceptibility gene in this region. METHOD: Mutation

screening of positional candidate genes was performed in two stages. The first

stage involved identifying, in unrelated subjects showing linkage to 2q24-q33,

genetic variants in exons and flanking sequence within candidate genes and

comparing the frequency of the variants between autistic and unrelated

nonautistic subjects. Two single nucleotide polymorphisms (SNPs) that showed

evidence for divergent distribution between autistic and nonautistic subjects

were identified, both within SLC25A12, a gene encoding the mitochondrial

aspartate/glutamate carrier (AGC1). In the second stage, the two SNPs in

SLC25A12 were fur! ther

genotyped in 411 autistic families, and linkage and association tests were

carried out in the 197 informative families. RESULTS: Linkage and association

were observed between autistic disorder and the two SNPs, rs2056202 and

rs2292813, found in SLC25A12. Using either a single affected subject per family

or all affected subjects, evidence for excess transmission was found by the

Transmission Disequilibrium Test for rs2056202, rs2292813, and a two-locus G*G

haplotype. Similar results were observed using TRANSMIT for the analyses.

Evidence for linkage was supported by linkage analysis with the two SNPs, with a

maximal multipoint nonparametric linkage score of 1.57 and a maximal multipoint

heterogeneity lod score of 2.11. Genotype relative risk could be estimated to be

between 2.4 and 4.8 for persons homozygous at these loci. CONCLUSIONS: A strong

association of autism with SNPs within the SLC25A12 gene was demonstrated.

Further studies are needed to confirm this association an! d to

decipher any potential etiological role of AGC1 in autism.

May 1, 2004

Jay,

The SLC25A12 finding is likely to be similar to the findings about

pro-celiac alleles, weak MTFHR alleles, weak GSH alleles, null alleles

of C4b, etc. As previously written, " The pro-celiac alleles are more

prevalent among folks with celiac, even as many and perhaps most folks

with the pro-celiac alleles don't develop celiac disease. This

relationship is similar to the allele findings I've seen at the recent

DAN! conferences. Many kids w/o autism have the impaired alleles (eg,

MTHFR), even as some of the impaired alleles occur with a slightly

higher frequency among kids with autism. "

Earlier today, Derrick asked an essential question: " We keep

accumulating information, but how does it help the much beleagured

clinician? "

Several physicians have asked me, where is the balance for parents with

limited funds? Should they invest in genomics testing at this time?

Would a weak-allele finding in a child alter therapy if, for many kids,

the same pathway can be adversely impacted by acquired reasons (eg, low

GSH due to low AAs and low minerals due to chronic gastro pathology)? In

other words and for example, circa 2004, regardless of a given MTHFR

weak allele or not, the same supplement and injection therapies may be

warranted and helpful. Thus the parent's limited funds may be better

spent on mB12, supplements, AA follow ups, OAT, etc.

In contrast, from a research perspective and in regard to proving why

the various autism therapies are helpful, the genomic findings are

extremely important, and even their softness is important, because

what's so strongly implicated are the role of environmental factors and

the role of timings and bunchings of environmental factors.

Regarding the SCL25A12 gene's association with autism: the finding

reinforces other mito findings in autism and also reinforces the various

therapies that I hear interpreted by some physicians and by some parents

as, we're hoping via this therapy (eg, therapies, X, Y, and Z) to

improve mito function. A converse of that logic is, Can acquired

pathologies impair mito function? Can supplements and other therapies

reverse those acquired mito impairments? Also, would a weak genetic

allele (eg, SLC25A12) create intro-mito conditions that can be

alleviated via supplements, vitamins, etc?

Consider celiac disease, what's more important: proving that the

individual has one of the pro-celiac alleles or removing gluten? The

first option provides no clinical improvement. Regardless of the genomic

background, removing gluten helps muchly.

jay krishnaa wrote:

>Linkage and Association of the Mitochondrial Aspartate/Glutamate r

SLC25A12 Gene With Autism Nicolas Ramoz, Ph.D., G. Reichert, B.Sc.,

J. , Ph.D., M. Silverman, Ph.D., Irina N. Bespalova,

Ph.D., L. , M.D., and ph D. Buxbaum, Ph.D.

>OBJECTIVE: Autism/autistic disorder (MIM number 209850) is a complex, largely

genetic psychiatric disorder. The authors recently mapped a susceptibility locus

for autism to chromosome region 2q24-q33 (MIM number 606053). In the present

study, genes across the 2q24-q33 interval were analyzed to identify an autism

susceptibility gene in this region. METHOD: Mutation screening of positional

candidate genes was performed in two stages. The first stage involved

identifying, in unrelated subjects showing linkage to 2q24-q33, genetic variants

in exons and flanking sequence within candidate genes and comparing the

frequency of the variants between autistic and unrelated nonautistic subjects.

Two single nucleotide polymorphisms (SNPs) that showed evidence for divergent

distribution between autistic and nonautistic subjects were identified, both

within SLC25A12, a gene encoding the mitochondrial aspartate/glutamate carrier

(AGC1). In the second stage, the two SNPs in SLC25A12 were further

> genotyped in 411 autistic families, and linkage and association tests were