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Can LaTKE cure APBD?
Building a Second Animal Model of APBD and Proof of Concept for ASO as a potential cure
Genetic Research/Targeted Therapies
Apbdrf saliva kit
Anti-Sense - Recently Approved Gene Therapy
High Throughput Screening (HTS) - New Technology Analyzes Treatment Compounds Fast
NYC Marathon fundraiser
Registry to Speed a Cure
Testing of molecules that may regulate Glycogen Branching Enzyme (GBE1)
POTENTIAL IMPACT OF APBD RESEARCH ON OTHER DISEASES
GBE - The Epicenter of the Problem
Personalized Medicine Initiative
Genetic Research/Targeted Therapies
Genetic Research/Targeted Therapies
Glycogen Branching Enzyme Mutations in the Jewish-American Population
Dr. Akman and Dr. DiMauro have submitted a proposal to determine the frequency of glycogen branching enzyme (GBE) mutations in the Jewish-American population. Their proposal has two specific aims.
Aim 1: To determine how often the typical Y329S genetic mutation occurs in samples provided by the main Jewish DNA repository in New York (DOR Yeshorim) by analyzing DNA sequences. To date 700 DNA samples have been received.
Aim 2: To find a second GBE1 mutation in patients who show typical signs and symptoms of APBD but only one proven Y329S mutation instead of the usual two, called Manifesting Heterozygote Phenomenon. Whole genome sequencing will be used (Columbia University Genome Center New York, NY).
What is Manifesting Heterozygote Phenomenon? APBD is most commonly caused by mutations in the GBE1 gene. This leads to a shortage of glycogen branching enzyme (GBE) which plays a part in storing glucose in a form called glycogen. The disease is usually inherited by receiving one mutated copy of the gene from each parent (autosomal recessive) so that both copies of the GBE1 gene in each cell have an error.
The mutations in both copies of the GBE1 gene can be identified in most APBD patients. However, using standard methods of gene sequencing, in about 40% of patients only one mutation can be identified, even though these patients have the same deficiency of glycogen branching enzyme and the same disease severity as people with mutations in both copies of the gene. A patient with this result is sometimes referred to as a ‘manifesting heterozygote’.
It is thought that the other copy of the brancher enzyme gene is also abnormal even though the abnormality cannot be detected using the common methods of gene sequencing. This mysterious abnormality of the brancher enzyme gene could be due to the complete absence of the gene, a mutation in the area that regulates the production of the gene, or more likely a mutation in the part of the gene that builds the template for making the brancher enzyme protein.
Identifying the other gene will help to more accurately diagnose APBD and open up new avenues of treatment.
Identification of APBD carrier gene frequency in Ashkenazi Jews
In August 2012, Dr. Marvin Natowicz published provocative results of an unexpectedly high frequency of APBD gene mutation in people of Ashkenazi Jewish background. His research found the mutation has a carrier frequency of 1 in 34.5 Ashkenazi Jews. Before this, APBD was considered a rare condition, with only 50 affected individuals described in the medical literature. There are now about 100 known cases. If Dr. Natowicz's results are validated, little known APBD would have a similar carrier frequency to Tay-Sachs disease.
We are interested in validating Dr. Natowicz’s research in order to continue to build awareness of the disease among physicians and researchers.
This will support early correct diagnosis of APBD and speed the development of effective treatments.
July 21, 2013
- Dr Akman is trying to find a second mutation responsible for low GBE activity. This mutation is not as severe as common Y329S or second rare R515 mutation. He has come to this conclusion based on messenger RNA (mRNA) studies. The mRNA molecule caries information from DNA to ribosomes for production of enzymes. Unlike DNA sequences mRNA sequence analysis shows that they carry only one message from the genomic DNA and unfortunately it is the mutated one. This mutation is currently undetectable by conventional DNA analysis, therefore his lab is studying the identify of this mutation. Finding this second mutation will allow him to diagnose carriers or patients with APBD at molecular level before the disease occurs. In addition, the diagnostic nature of this mutation may allow us to design a therapy with new antisense oligonucleotide technology.
The Manifesting Heterozygote Conundrum
While our genetic research goes on at full capacity, we don't have yet an answer for the manifesting heterozygote conundrum. Our estimation is that the phenomenon of differential allelic expression in manifesting heterozygotes is much more complicated than initially assumed. This further complication unfolds as our research progresses. The main complications are the following: Our recent data reveal some new manifesting heterozygotes who lack the haplotype – a set of co-segragating genetic markers - so far found to be common in all manifesting heterozygotes. Furthermore, in the manifesting heterozygotes who initiated this research, the genomic DNA is heterozygous for the c.1076A>C (p.Y329S) mutation, meaning one chromosome has the mutation and the other one has the wild type base pair at the same location. At the mRNA (or complementary DNA (cDNA)) level, however, only the mutated c.1076A>C variant was observed, suggesting either reduced transcription of the non-c.1076A>C-mutated allele, or possibly its instability which might lead to quick degradation. This mRNA is termed homozygous for the c.1076A>C (p.Y329S) mutation. As opposed to these “classical” manifesting heterozygotes, we have also recently discovered other manifesting heterozygotes where both cDNA and genomic DNA are heterozygous for c.1076A>C. Unexpectedly, these manifesting heterozygotes are haplotypically identical to the ones whose cDNA is homozygous for c.1076A>C (p.Y329S). At the moment, we are exploring new directions in order to try and solve this conundrum: We are testing the possibility that while, based on established search engines, the polymorphisms discovered in the non-mutated allele are not bona fide modulators of gene expression, they might still affect gene splicing - the pre-mRNA modifications which determine which introns are removed and which exons will remain in the final mRNA. This possibility is currently being tested by a method called multiplex ligation-dependent probe amplification (MLPA), basic PCR and gel electrophoresis of manifesting heterozygote transcripts and allele-specific expression analysis using real time RT-PCR with customized primers and probes. We are very interested in finding whether all (or most, see above) manifesting heterozygotes share the same haplotype we found. We encourage researchers to send us DNA samples from their manifesting heterozygous patients in order to help us in this important genetic research.