Lab 4 Structural Chromosome Abberations PDF

Structural Chromosoma l Aberrations Chromosomal Aberrations Any kind of alteration in the genetic information (Chromosomes) can have a deleterious eff ect on the organism. These alterations can be the manifestation of variations in the number of chromosomes (discussed in another chapter) or alter...

Structural Chromosoma l Aberrations Chromosomal Aberrations Any kind of alteration in the genetic information (Chromosomes) can have a deleterious eff ect on the organism. These alterations can be the manifestation of variations in the number of chromosomes (discussed in another chapter) or alterations in the chromosomal structure.  Backgroun Structural d Numerical (Aneuploidy) Aberrations Change to number of chromosome Structural Change to a specific part of the chromosome Deletio Inversio Structural n​ Aberrations n Duplicatio Translocatio Polyploid Aneuploidy ​ n​ n y Inversion  Inversion Chromosome inversions are defi ned as the rearrangement produced by two break-points within the same chromosome, with the subsequent inversion and reinsertion of this fragment.  Inversion if the inverted fragment Pericentric includes the chromosome’s centromere Chromosome inversions may be if the inverted fragment does not include the Paracentric chromosome’s centromere. The frequency in the general population of chromosome inversions is 1–5 in 10,000 for paracentric inversions and 1–7 in 10,000 for pericentric inversions.  Inversion In most cases, being a carrier of a chromosome inversion has no direct health implications. However, carriers of a balanced Robertsonian translocation have some reproduction implications, due to imbalanced gametes: Offspring with an Reproduction issues:​ unbalanced chromosome rearrangement: Sterility/infertility;​ In unbalanced pericentric inversions: Recurrent pregnancy losses (in formation of recombinants with deletion and 3%–9% of couples with duplication of the inverted segment; recurrent pregnancy losses).​ In unbalanced paracentric inversions: inverted duplications of the segments Deletion  Deletio n In deletion the daughter chromosome loses a part of chromosome compared to parent chromosome, and this deleted part of chromosome is degraded and completely lost, which makes this kind of mutation irreversible Human disorders caused by deletion of large segment of chromosome are usually the cases in which deletion occurs in heterozygous individuals as the deletion in homozygous would result in lethal condition.  Deletio n Types of deletion: Terminal Deletion - a deletion that occurs towards the end of a chromosome. Intercalary Deletion - a deletion that occurs from the interior of a chromosome.  Deletio n Terminal Deletion :A single break at the terminal portion of chromosome causes the loss of genetic material. Example: 1- Wolf-Hirschhorn syndrome 2- Cri-du Chat Syndrome Wolf-Hirschhorn syndrome Deletion of genetic material near the end of the short (p) arm of chromosome 4. NSD2, LETM1, and MSX1 are the genes that are deleted in people with the typical signs and symptoms of this disorder. These genes play signifi cant roles in early development. Symptoms: 1- Greek helmet face 2- Mental Retardation 3- Frequent Seizures 4- Microcephaly 5- Cardiac, renal and genital abnormalities Wolf-Hirschhorn syndrome NSD2 gene is associated with many of the characteristic features of Wolf- Hirschhorn syndrome, including the distinctive facial appearance and developmental delay. Deletion of the LETM1 gene appears to be associated with seizures or other abnormal electrical activity in the brain. The loss of the MSX1 gene may be responsible for the dental abnormalities and cleft lip and/or palate that are often seen with this condition.​ Cri-du chat syndrome Cri-du-chat syndrome is caused by a deletion of the end of the short (p) arm of chromosome 5 (5p-) Researchers believe that the loss of a specifi c gene, CTNND2, is associated with severe intellectual disability in some people with this condition. Symptoms: 1-A high-pitched, cat-like cry or weak cry 2-low birth weight 3-small head 4-broad, fl attened bridge of the nose 5-eyes spaced wide apart 6-folds of skin over the eyelids Cri-du chat syndrome The CTNND2 gene provides instructions for making a protein called delta-catenin. This protein is active in the nervous system, where it likely helps cells stick together (cell adhesion) and plays a role in cell movement. In the developing brain, it may help guide nerve cells to their proper positions as part of a process known as neuronal migration.  Deletio n Intercalary Deletion: An intermediate segment of the chromosome is lost, leaving the ends of the chromosome intact. This is the result of two breaks in the chromosome followed by the union of the two ends Example: 1- Prader-Willi syndrome (PWS) and Angelman syndrome (AS) 2-William's disease Prader-Willi syndrome Multisystem, contiguous gene disorder caused by an absence of paternally expressed genes within the 15q11.2-q13 region via deletion of the paternally inherited. Symptoms: (Infants) 1- Poor muscle tone 2- Underdeveloped genitals. 3- Almond-shaped eyes 4- Narrowing of the head at the temples 5- Turned-down mouth and a thin upper lip 4- Generally poor responsiveness  If the previously mentioned mutation occurred on the maternal chromosome. It results in another syndrome Angelman syndrome (AS) is a rare neuro -genetic disorder that occurs in one in Angelman syndrome (AS) 15,000 live births or 500,000 people worldwide. (deletion in chromosome 15) It is caused by a loss of function of the UBE3A gene in the 15th chromosome derived from the mother. Symptoms: 1- Being restless (hyperactive) 2- Having a short attention span. 3- A wide mouth with widely spaced teeth 4- Tendency to stick the tongue out 5- A side-to -side curvature of the spine  UBE3A, the gene that encodes E6AP, is a protein that is expressed in an imprinted Angelman syndrome (AS) manner in the brain. Genomic imprinting marks the parental origin of chromosomal subregions and results in allele-specifi c diff erences in DNA methylation, transcription, and replication. Within the chromosome region 15q11-q13, the gene UBE3A is imprinted specifi cally in the brain, resulting in maternal expression of E6AP in the human fetal brain and adult cortex, while the paternal copy is silenced.  William's syndrome Williams Syndrome is caused by microdeletion at 7q11.23. This condition is characterized by mild to moderate intellectual disability or learning problems, unique personality characteristics, distinctive facial features, and heart and blood vessel (cardiovascular) problems. Symptoms: (Infants)​ 1- Chronic ear infections and/or hearing loss. ​ 2- Dental abnormalities, such as poor enamel and ​ small or missing teeth.​ 3- Endocrine abnormalities: hypothyroidism, early puberty and ​ diabetes in adulthood.​ 4- Scoliosis (curve of the spine).​ 5- Unsteady walk (gait).​ Translocation Translocation It is the shuffl ing of genetic material along the length of chromosomes. The inter-chromosomal translocation involving two nonhomologous chromosomes, one donor and the other recipient chromosome 20 There are 2 types of translocation: 20 a- Reciprocal Translocation b- Robertsonian Translocation Translocation Reciprocal Translocation Reciprocal translocations are the transfer of genetic material between homologous chromosomes. These are the most balanced exchanges, such that no genetic material is lost, and individuals are phenotypically normal. A prototypical example of this phenomenon is represented by the Philadelphia chromosome associated with acute lymphocytic leukemia and chronic myelogenous leukemia Translocation Example 1: Philadelphia chromosome. A piece of chromosome 9 and a piece of chromosome 22 break off and trade places. The BCR- ABL gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called the Philadelphia chromosome. This translocation results in a fusion gene called the BCR-ABL gene. Translocation Example 1: Philadelphia chromosome. ABL This gene is a protooncogene that encodes a protein tyrosine kinase involved in a variety of cellular processes, including cell division, adhesion, differentiation, and response to stress. The activity of the protein is negatively regulated by its SH3 domain, whereby deletion of the region encoding this domain results in an oncogene. BCR-ABL Fusion gene BCR-ABL1 oncogene that encodes the chimeric BCR-ABL1 protein with constitutive strong tyrosine kinase activity and this activity is the significant molecular biological basis for the pathogenesis of these diseases. Translocation Robertsonian Translocation Robertsonian translocations (RobT) result from the breakage of two acrocentric chromosomes (13, 14, 15, 21, and 22) and subsequent fusion of their long arms to form one derivative chromosome. The short arms are lost, and the total chromosome number is reduced to 45. Genetically balanced carriers of these translocations have an increased incidence of infertility as well as a risk for genetic imbalances among their offspring. The risk of Down syndrome (trisomy 21) and Patau syndrome (trisomy 13) is elevated in the offspring of the rob(14;21) and the rob(13;14) balanced carriers Translocation Robertsonian Translocation & Down Syndrome Approximately 4% of Down syndrome patients have 46 chromosomes, one of which is a Robertsonian translocation between chromosome 21q and the long arm of one of the other acrocentric chromosomes (usually chromosome 14 or 22). The translocation chromosome replaces one of the normal acrocentric chromosomes, and the karyotype of a Down syndrome patient with a Robertsonian translocation between chromosomes 14 and 21 is therefore 46,XX or XY,rob(14;21)(q10;q10),+21 Translocation Robertsonian Translocation & Down Syndrome Despite having 46 chromosomes, patients with a Robertsonian translocation involving chromosome 21 are trismic for genes on the entirety of 21q Duplication Repetition of a segment of chromosome containing several genes. Depending upon the location and orientation of the duplicated segment, the duplication can be divided into several categories The Most important are: 1- Tandem Duplication 2- Non-Tandem Duplication Examples: 1- Charcot-Marie-Tooth disease type 1A Duplication Example 1: Charcot-Marie-Tooth disease type 1A This is a type of inherited neurological disorder that affects the peripheral nerves. CMT1A is caused by having an extra copy (a duplication) of the PMP22 gene. PMP22 The PMP22 gene provides instructions for making a protein called peripheral myelin protein 22 (PMP22). This protein is found in the peripheral nervous system, which connects the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. PMP22 PMP22 plays a crucial role in the development and maintenance of myelin. Studies suggest that the PMP22 protein is particularly important in protecting nerves from physical pressure, helping them restore their structure after being pinched or squeezed (compressed). The PMP22 gene also plays a role in the growth of Schwann cells and the process by which cells mature to carry out specifi c functions (diff erentiation).