GENETIC DISORDERS

(Mutations & Mendelian Disorders)

Dr. Shahab Riaz

Generalized Classification of Human Diseases

• Environmentally Determined

• Genetically Determined

• Both Environmental and Genetic factors

• Hereditary Disorder: The disorder derived from one’s parents.

• Familial Disorder: The hereditary disorder transmitted in the germ

line through the generations.

• Congenital Disorder: Simply implies “Born With”. Some congenital

diseases are not genetic e.g., congenital syphilis. Similarly not all genetic diseases are congenital e.g.,

Huntington’s Disease age 20s-30s

MUTATIONS

• Permanent change in the DNA or Genome.

• Germ cell mutations progeny inherited diseases

• Somatic cell mutations don’t cause hereditary diseases but some cancers / congenital malformations

Mutation Classification

1. Genome Mutations: Loss or gain of whole chromosomes monosomy or trisomy

2. Chromosome Mutations: Rearrangement of genetic material visible structural changes in

chromosome

1 and 2 transmitted infrequently bcz most incompatible with life

3. Gene Mutation: - Most of the mutations associated with hereditary diseases - Partial or complete deletion of a gene - OR more often a single base is affected

Genome Mutation

Genome Mutation

Chromosome Mutation

Gene Mutations Classificationa. Point Mutation (Single Base Substitution): A single nucleotide base is substituted by a different base

b. Frameshift Mutation (Framing Error): (Less common) caused by “indels” one or two base pairs may be

inserted into or deleted from the DNA alterations in the reading frame of the DNA strand bcz triplet nature of coding codons

- number of nucleotides is not evenly divisible by three from a DNA sequence

- completely different translation from the original

c. Trinucleotide Repeat Mutations:

Point Mutation

Frameshift Mutation

Trinucleotide Repeat Mutations• Special category of mutations

• Amplification of a sequence of three nucleotides

• Although the specific nucleotide sequence differs in various disorders but most have “C” and “G”.

• E.g., Fragile-X syndrome (prototypic of this category) 250-4000 tandem repeats of sequence CGG within a gene called FMR-1

• In normal populations small number average 29 repeats

• Abnormal expression of FMR-1 gene mental retardation

• Dynamic feature of TRMs amplification during gametogenesis

Point Mutations Classification

• Transitions: (more common) replacement of a purine base with

another purine or replacement of a pyrimidine with another pyrimidine

• Transversions: replacement of a purine with a

pyrimidine or vice versa.

General Principles of Effects of Gene Mutations

• Point Mutations within Coding Sequences (Exons): Code altered in triplet bases by single base substitution

If this mutation alters the meaning of genetic code and codes for a different amino acid Mis-sense Mutations

If substituted amino acid causes little change in protein function “Conservative” Mis-sense Mutation

If normal amino acid replaced by a very different one “Non-conservative” Mis-sense Mutation

If point mutation changes an amino acid codon to a chain termination or Stop Codon Non-sense Mutations

If codes for different amino acid but no functional protein change Silent Mutations

For example, sickle-cell disease is caused by a single point mutation (a missense mutation) in the beta-hemoglobin gene that converts a GAG codon into GTG, which encodes the amino acid valine rather than glutamic acid.

General Principles of Effects of Gene Mutations

• Mutations within Non-coding Sequences (Introns): Deleterious effects may also result even if exons not involved

Most often without consequences, although there are exceptions

Promoter & Enhancer sequences upstream or downstream of gene

If point mutations or deletions regulatory sequences interfere with binding of transcription factors marked reduction or total lack of transcription

If the mutation occurs in the splicing seat of an intron interfere with

correct splicing of the transcribed pre-mRNA failure to form mature mRNA no translation no gene product synthesis

General Principles of Effects of Gene Mutations

• Deletions & Insertions: Small deletions or insertions involving coding sequence

alterations in reading frame of DNA strand Frame Shift Mutations

If base pairs are three or multiple of three no frame shift

Instead an abnormal protein missing one or more amino acids is synthesized

(Paradox) Protection by Mutations

• Uncommonly the mutations may be protective

e.g.,

HIV uses chemokine receptor CCR5 to enter cells deletion in CCR5 gene protection from HIV infection

Mendelian Disorders

• All Mendelian disorders result of expressed mutations in single genes of large effect

• Neither multifactorial inheritance nor chromosomal disorders

• Every individual 5-8 deleterious genes most recessive no phenotypic effect

• 80-85% of these mutations are familial remainder new mutations acquired de novo by affected individual

Mendelian Disorders

• Some autosomal mutations partial effect in heterozygotes full expression in homozygotes

• Sickle cell anemia HbA replaced by HbS Homozygotes all Hb of HbS type (full blown sickle cell anemia)

• Heterozygotes partial HbS , partial HbA sickling and anemia in O2 tension (Sickle Cell trait)

• Aside from Dominant and Recessive “Codominance” both alleles of a gene pair fully expressed in a heterozygote e.g., blood group antigens

Mendelian Disorders

• Pleiotropism: when a single mutant gene leads to many end-effectse.g., sickle cell HbS , sickling, hemolysis, logjam in small vessels, splenic

fibrosis, organ infarcts, bone changes

• Genetic Heterogeneity: when mutations at several genetic loci produce the same effect or traite.g., profound childhood deafness any of 16 different types of autosomal

recessive mutations

• Polymorphism: not all nucleotide changes produce genes that cause disease

when such DNA change occurs in at least 1% of population called Polymorphism

Transmission Patterns of Single Gene Disorders

1. Autosomal Dominant

2. Autosomal Recessive

3. X-linked