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Molecular Work | |
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Initial Discovery and Clinical Aspects Molecular/Biochemical Properties and Characteristics of Cri Du Chat-Related Proteins Links to Cri Du Chat Support Groups
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There has been a lot of
molecular genetics work done on Cri Du Chat Syndrome (CdCS), as it is one
of the most common deletion syndromes which is about 1:20,000 to 1:50,000
births (found by Niebur, 1978) (OMIM). Since CdCS can occur whether a
child is missing only one short portion of the p arm of the 5th
chromosome or missing the whole p arm, there is not one specific gene that
is the cause of the syndrome. When a baby is born with such
characteristics mentioned in the diagnostics section, the doctors are
suspecting CdCS and test for it using the techniques described. · CdCS was discovered by Lejeune et al. in 1963 when a child was born having the distinctive cat-like cry associated with the syndrome. Lejeune found that “approximately 12% of the deletions result from unbalanced segregation of translocations or recombination involving pericentric inversion of one of the parents.” (OMIM) · Then in 1988, Caccichetti et al. found a baby that had CdCS (the cat-like cry) but none of the phenotypic characteristics of CdCS. The group did testing on the baby and discovered that the cat-like cry is due to a deletion at the p15.32 of the 5th chromosome. (OMIM) This group also found that people who suffer from CdCS that live to be adults will have an “IQ below 20, a loss of hypertelorism an epicanthic folds, and development of a thin, narrow face with prominent nasal bridge.” (OMIM) · Overhauser et al. found in 1994 that the “chromosomal region that is involved with the remaining features of CdCS were mappted to a small region within central 5p15.2” by studying the 5p deletions of 49 individuals using somatic cell hybrids. This explains how the deletion of the entire p arm of the 5th chromosome or a small deletion of this p arm in this region can both cause CdCS. In the next year, 1995, Gersh et al. performed FISH (fluorescence in situ hybridization) using lambda phage and cosmid clones to determine the specific region of the 5p arm that was deleted from 4 different families. The group’s findings were consistent with previous work, proving that the “breakpoints were located distal to the 5p15.2 region.” (OMIM)
(Picture from http://www.criduchat.asn.au/criduchat/what.htm) One can see the map of the chromosome of the region 5p15.31-5p15.2 from the NCBI site here. · Further study on CdCS includes trying to determine the exact regions of the p arm of the 5th chromosome that lead to phenotypic differences in CdCS patients. Cerruti Mainardi et al. studied group of 80 patients with CdCS with a wide variety of different deletions of their 5p arm ranging from p13 to p15.2. The group “identified a critical region at 15.2 for dysmorhism and metal retardation and a separate region at p15.3 for the cat-like cry, this region being bounded by the markers at D5S13 and D5S731. They also suggested a separate region at p15.3 for speech delay.” (OMIM) As one can see, not all CdCS patients will have the same phenotypic characteristics, as some may be missing more of the 5p arm than others. · Then in 2003, Zhang et al. studied the effect of a CdCS patient without the 5p15.33 region of the 5th chromosome where the TERT gene is located. This gene produces a protein that “is the rate-limiting component for telomerase activity, which is essential for telomere length maintenance and sustained cell proliferation.” (OMIM) The deletion of this allele will cause a CdCS patient to have “haploinsufficiency for telomere maintenance in vivo [which] may be one genetic element contributing to the phenotypic changes in CdCS.” (OMIM) · The Zhang et al. group further studied specific CdCS patients who had the characteristic cry, speech delay, facial dysmorpholgy, and level of mental retardation in 2005. They “used array comparative genomic hybridization to map DNA copy number changes in 94 patients with CdCS” (OMIM) and these characteristics. “Genotype-phenotype correlations localized the region associated with the cry to 1.5 Mb in distal 5p15.31, between BACs containing markers D5S2054 and D5S676; speech delay to 3.2 Mb in 5p15.33-p15.32, between BACs containing D5S417 and D5S635; and the region associated with facial dysmorphology to 2.4 Mb in 5p15.31-p15.2, between BACs containing D5S208 and D5S2887.” (OMIM)
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