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When Leilah* began showing the dreaded symptoms at age 8, her parents quickly turned to the medical community for help. Having earlier lost two children to this mysterious disease, they recognized its signs. She was diagnosed with polymorphic ventricular tachycardia (PVT) a fatal heart condition. Primarily affecting young children, PVT is characterized by a fast and irregular heartbeat, seizures, and in certain cases, sudden death - particularly following physical exertion or emotional stress.
The child's family belongs to a Bedouin community in the north of Israel thought to be the descendants of three brothers who settled in the Galilee over 200 years ago. The nature of the disease and the common Bedouin custom of familial intermarriage alerted researchers to possible genetic involvement.
Hypothesizing that one of the original brothers had harbored a genetic mutation, doctoral student Hadas Lahat of the Danek Gartner Institute of Human Genetics, Sheba Medical Center visited the community and tested the families. It appeared she was on the right track. In seven families alone, thirteen children were identified as having PVT and treated. Nine untreated children in these families had earlier died from this condition.
The Sheba team succeeded in pinpointing a region in human chromosome 1 that most likely gave rise to the disease when mutated, and showed that the defective gene was recessive. However the suspect area encompassed over 100 genes, making it nearly impossible to identify the exact gene responsible for PVT. At the time the Human Genome Project was far from complete and information was available for only half of the 100 suspect genes. Lahat and her advisers, Prof. Michael Eldar, Chief of the Heart Institute at the Sheba Medical Center, and Dr. Elon Pras of the Danek Gartner Institute of Human Genetics, decided to contact the Weizmann Institute of Science for help.
At the Institute, Drs. Nili Avidan, Edna Ben-Asher, and Tsviya Olender, and Prof. Doron Lancet of the Department of Molecular Genetics initially had little success. Indeed, after screening a dozen of the more seemingly biologically relevant genes, the team was quite discouraged. Then, having systematically screened every genome database update, Dr. Olender suddenly came across a perfect candidate gene, Calsequesrin 2 (CASQ2), previously not known to belong to this genomic region. This protein appeared a likely candidate because it serves as a calcium ion reservoir in heart muscle cells. Since it binds, holds, and releases calcium ions, the CASQ2 protein could possibly play a vital role in the contraction and relaxation of heart muscles. A second clue came from an unexpected source. Only four months earlier a different research team had found that a mutation in another gene, known as RYR2, also causes a form of PVT. Importantly, RYR2 takes part in the same cellular pathway as CASQ2.
The Weizmann Institute team soon found that the children suffering from PVT had a mutation in their CASQ2 gene and were able to pinpoint how things had gone wrong in those that had died. They discovered that the mutation was surprisingly small - characterized by only a single base change, from G to C, in one of the DNA's nucleotides, which changes the amino acid coded, from aspartic acid to histidine.
But how can a single amino acid change have such a devastating outcome? The CASQ2 protein carries a very strong negative charge, thus binding a large number of positively charged calcium ions and releasing them when necessary (thereby triggering the muscle contractions through which the heart pumps blood throughout the body). Unfortunately, in the mutated CASQ2 protein, the overall negative charge is smaller, given that the single base change replaces the aspartic acid - which is negatively charged - with the positively charged histidine. This most likely damages the protein's ability to attract calcium ions, leading to heart failure.
'Our finding is expected to improve the screening for and treatment of this fatal disease, as well as opening a window to a better understanding of other heart conditions,' says Dr. Avidan, who champions the mutation discovery effort in the Weizmann team. 'We believe that mutations in this and other biochemically related genes may lie behind a number of as yet largely unsolved heart disorders.'
Published in the American Journal of Human Genetics, the successful collaboration between the Sheba Medical Center and the Weizmann Institute illustrates how cracking a genetic riddle may save lives. Every solved puzzle sheds light on the role genes play in health and disease, and on the potentially immense future contribution of genetically based drugs.
The research performed at the Weizmann Institute of Science was funded by the Crown Human Genome Center. Other scientists collaborating in this study are Etgar Levy-Nissenbaum and Dr. Boleslaw Goldman of the Danek Gartner Institute of Human Genetics, Sheba Medical Center, and Drs. Asad Khoury and Avraham Lorber of the Rambam Medical Center.
Both parents carry a normal gene R and a faulty gene r. The parents (Rr genotype, are unaffected carriers, because having one R copy assures health. One quarter of the offspring, who happen to receive a faulty gene from both parents (rr) will have a disease, while the rest will be unaffected.
An affected parent (genotype Dd) has a single faulty dominant gene (D), which overpowers its normal counterpart (d). When mating with an unaffected parent (dd), half of their offspring will have the disease (Dd) and the other half will be unaffected (dd).
- An estimated 40,000 genes are dispersed through 23 chromosome pairs.
- It is impossible to see the 23 chromosome pairs with the unaided eye, yet this set contains roughly 3.1 billion base pairs - an amount of data roughly equivalent to 200 telephone directories, each 500 pages long.
- Only 3 percent of the genome code for proteins, the rest (sometimes termed 'junk DNA') might serve other, as yet unclear, functions.
- The human genome differs from Chimp DNA by only 1.5% and shares about a third of its genes with Drosophila melanogaster - the common fruit fly. One fly gene with a human counterpart is p53, a tumor suppressor gene that is mutated in over 50 percent of all cancer patients.
- The Human Genome Project is a technology triumph. New robots put to work in the last two years have increased the sequencing rate tenfold, enabling the sequencing of the entire human genome in one year.
Prof. Lancet holds the Ralph and Lois Silver Professorial Chair in Human Genomics. His research is supported by the Wolfson Family Charitable Trust; the Crown Human Genome Center; the Henri and Francoise Glasberg Foundation; the Alfried Krupp von Bohlen und Halbach Foundation; the Kalman and Ida Wolens Foundation; and Mr. Avraham Goldwasser, Israel.