Category Archives: Genetics

Gonadal Mosaism

Gonadal Mosaism

What is the cause of gonadal mosaism?

Results from de novo mutation in the cells destined to form the gonads. (ie. the new mutation is confined to the gametes.)

Eg. phenotypically normal parents with several children who have osteogenesis imperfecta.

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Genomic Imprinting

Genomic Imprinting

Difference between maternal and paternal imprinting?

Maternal imprinting results in transcriptional silencing whereas paternal imprinting results in inactivation of the gene.

Methylation is involved in inactivation.

Inheritance pattern in genomic imprinting, epigenetic, syndromes:

In Prader-Willi syndrome there is a deletion in the paternal chromosome 15. Maternal transcriptional silencing occurs at this same region.

Since there is already imprinting of the maternal gene (transcriptional silencing) the last only remaining copy of the gene is no longer functional.
The opposite is true in Angelman syndrome.
Note the Angelman and Prader-Willi gene are in close approximation on chromosome 15.

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Mitochondrial Gene Mutations

Mitochondrial Gene Mutations

MUTATIONS IN MITOCHONDRIAL GENES

How are these mutations transmitted?

- mitochondrial DNA, mtDNA, is transferred from the mother by meiosis

What genes are involved?

- genes encoding enzymes involved in oxidative phosphorylation, such as in Leber hereditary optic neuropathy

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Non-Mendelian Inheritance

Non-Mendelian Inheritance

Different types of non-Mendelian inheritance:

1  Trinucleotide expansions

2. Mitochondrial mutations

3. Imprinting

4. Gonadal mosaism

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Trinucleotide repeat expansion diseases

Trinucleotide repeat expansion diseases:

1. Fragile X syndrome

2. Huntington

3. Friedrich ataxia

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Cytogenetics

Cytogenetics

Causes of aneuploidy:

1. Non-dysjunction

2. Anaphase lag

3. Mosaism

4. Translocation

Types of chromosomal rearrangments:

1. Translocation (balanced and Robertsonian)

2. Isochromosome

3. Inversion (pericentric, paracentric)

4. Ring chromosome

5. Deletion

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Glycogen Storage Diseases

Glycogen Storage Diseases

Glycogenoses, Glycogenosis

Types of Glycogen Storage Diseases:

- Hepatic (von Gierke)

- Myopathic (McArdle)

- Generalized (Pompe)

- cardiomegaly, hypotonia, HM, die in infancy

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Mucopolysaccharidosis

Mucopolysaccharidosis

Mucopolysaccharidosis diseases (MPS)

- deficiency in enzymes that degrade GAG (heparin sulfate, keratin sulfate, dermatin sulfate, chondroitin sulfate)

“H and S”

- phagocytic cells

- Hunter and Hurler syndromes (iduronidase)

- Hepatosplenomegaly

- Skeletal deformities (coarse facies)

- Subendothelial deposits (especially coronaries)

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Lysosomal Storage Diseases

Lysosomal Storage Diseases

Tay Sachs Disease

A Sphingolipidosis

- gangliosidase

- gangliosides

- ganglion cells

- GM2

- hexoaminidase A

- accumulation of GM2 gangliosides in lysosomes

- whorled vacuoles in neurons and ganglion cells in retina → cherry red spot on macule

- fat stains (oil red O and  Sudan black)

- die by the age of 3

Niemann Pick Disease

- spingomyelinase deficiency

- distention of lysosomal vacuoles with sphingomyelin in liver, brain, spleen (stored in neurons and in phagocytic cells)

- HSM

- gyri thinned, sulci widened → mental retardation

- die within 1-2 years of age

Niemann Pick Disease Summary:

- cell membranes

- sphingomyelinase

- sphingomyelin

- phagocytic cells

- vacuoles

- fat stains (oil red O and  Sudan black)

- gyri, sulci

Gaucher’s Disease

Gaucher’s Disease is the most common lysosomal storage disease

- most common lysosomal storage disease

- Glucocerebrosidase mutation

- Glucocerebroside

- Phagocytic cells (spleen, liver, bone marrow, lymph nodes, thymus, peyer patches) affected

- characteristic big spleen due to accumulation of defective phagocytic cells

- Gaucher cells (crumpled tissue paper)

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Types of Mutations

Genetic Mutations

Types of mutations

·    Point mutations (substitution), deletion, insertion, frameshift mutation

·    Trinucleotide repeat expansion (eg. fragile X syndrome is an expansion of the FMR1 gene)

·    Mutations to non-coding sequence of DNA (eg. to binding sites of transcription factors)

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