2/ Diseases caused by mutations in receptor proteins Familial hypercholesterolemia (FHC) Autosomal dominant disorder with incidence of 1 in 500 in general population. Mutation affects receptors for low-density lipoprotein LDL, which represent 70% of the total plasma cholesterol. FHC results in early xanthelasma, atherosclerosis & IHD. Heterozygous FHC increases cholesterol 2-3 fold which is asymptomatic till adult life, while homozygous form results in 5 fold or more increase & appear early in childhood who die of MI at teen ages.

Diseases caused by defects in transport system In cystic fibrosis, there is defective transport of chloride ions in exocrine glands, sweat glands, lungs and pancreas

3/ Diseases caused by mutations in enzyme proteins Enzyme defects Mutation may result in the synthesis of a defective enzyme with reduced activity or in reduced amount of normal enzyme S E1 I 1 E2 I 2>M 1>M 2 E3 P

4/ Defects in proteins that regulate cell growth Mutations in proto-oncogenes and tumor-suppressor genes causing neoplasia Cancer-causing mutations usually affect somatic cells, only 5% of cancers are familial, mostly autosomal dominant

5/ Genetically determined Adverse reaction to drugs Certain genetically determined enzyme deficiencies are unmasked only after exposure of the affected individual to certain drugs. This special area of genetics is called pharmacogenetics. A classic example is G6PD deficiency.

B/ Cytogenetic disorders (Chromosomal abnormalities) Incidence is 1: 200 newborn, but it is much higher during pregnancy (50% in the first trimester abortions). Chromosomal features with position of the centromere is used for diagnosis of chromosomal abnormalities.

Karyotype (study of chromosome): is the photographic representation of a stained metaphase chromosomes, which are arranged in sets of homologous pairs largest to smallest.

The study of chromosomes-karyotyping is the basic tool of the cytogeneticits. The usual procedure is to arrest mitosis in dividing cells in metaphase,. The most commonly used stain is Giemsa, hence called G banding. In a banded karyotype, each chromosome has 2 arms p and q (short and long). Each arm is divided into 2 or more regions by prominent bands. The regions are numbered from the centromere outward. Each region is further subdivided into bands and sub-bands and these are ordered numerically as well.

Identification of chromosomes: Each human chromosome is numbered from 1-22, and sex chromosomes either X or Y p arm (short arm) Centromere q arm (long arm) Example - 1q2.4 . The first chromosome, long arm, second region of the chromosome, the fourth band of that region

Fluorescent in situ hybridization (FISH), has become an important tool to routine karyotyping. This technique can be used for nondividing cells (interphase nuclei). FISH can be used to demonstrate subtle microderangments in the structure of the chromosome. Chromosome painting is an extension of FISH, in which number of chromosomes can be visualized simultaneously. However, for the 46 chromosome to be visualized at the same time, Multicolored FISH (M-FISH) and spectral karyotyping (SKY) is used. It is called "spectacular karyotyping"

FISH technique, interphase nucleus, trisomy 21 (red)

FISH Technique- Multicolored FISH (SKY)

Cytogenetic disorders may result from alterations in the number (genome mutation) or structure (chromosome mutation) of one or more of chromosomes & may affect autosomes or sex chromosomes.

Numeric abnormalities (Genome mutation ) Human chromosomes are arranged in 23 pairs of chromosomes (46); 22 autosomes (matched pairs) & one set of sex chromosomes (male = unmatched pair, XY & female=matched pair, XX).

Haploid=n=23 Diploid=2n=46 Euploid is any exact multiple of the haploid number (x n). Polyploid is 3n (triploid=69) & 4n (tetraploid=92) & generally results in a spontaneous abortion. Aneuploid is any number that is not an exact multiple of n. The causes of aneuploidy are: Non-disjunction Anaphase lag

Aneuploid The chief cause of aneuploidy is non-disjunction of the homologous pair of chromosomes at the first meiotic division or failure of sister chromatids to separate during the second meiotic division, leading to the production of two aneuploid cells. When nondisjunction occurs, the gametes formed have either an extra chromosome (n+1) or one less chromosome (n-1).

Fertilization of such gametes by normal gamete will result in two types of zygotes: trisomic with extra chromosome (2n+1) (e.g., Down sy), or monosomic (2n-1) (e.g., Turner sy). Monosomy involving an autosome is incompatible with life, whereas monosomy involving sex chromosomes & trisomies of certain autosomes is compatible with life.

Aneuploid In anaphase lag, one homologous chromosome in meiosis or one chromatid in mitosis lags behind and is left out of the cell nucleus. The result is one normal cell and one cell with monosomy

47 2n+1 + 45 2n-1 24(n+1) 23 22(n-1) 46

Mosaicism Is a term used to describe the presence of two or more cell populations in the same individual (normal cells and monosomy or trisomy cells) Mosaicism affecting sex chromosomes is common. While autosomal variety is much less frequent.

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