Genes & HSP

The Beginner’s Guide to Genes, Mutations and Gene Testing

from a presentation by Dr. Marina Kennerson, Principal Hospital Scientist in Genetics, at the 2007 HSPRF Workshop


What is a gene?

A gene is a segment of DNA that codes for the synthesis of a protein. We can think of a gene as a paragraph that tells us information. The paragraph can be broken up into sentences (exons). The sentences can be broken down into three letter words (codons which tell us the amino acids used). Amino acids are the building blocks of proteins. All genes begin with a start codon and end with a stop codon.

Gene:

The sun was hot. The man did not get his hat. The hat was old.

Start codon……………………………………………………Stop codon

We can think of genes being made up of sentences with three letter words (codons denoting the amino acids) that provide information about which protein is being produced.

Genes contain exons:

The sun was hot. The man did not get his hat. The hat was old.

Each sentence represents an exon:

Exon 1 The sun was hot.

Exon 2 The man did not get his hat.

Exon 3 The hat was old.

What is a Mutation?

An error in the coding sequence of a particular gene results in the gene producing the wrong protein. The error is called a mutation. Over 40 HSP genes have been identified, some with a large number of mutations.  Gene tests are used to identify the mutation.

What is Gene Testing?

A genetic test is the analysis of human DNA, RNA, protein or certain metabolites in order to detect alterations related to a heritable disorder.

When you have talked with your doctor about a gene test and then a genetic counsellor, a decision is made on which gene or genes to have tested for the presence of a mutation. The diagnostic laboratory detects and describes the mutation in the gene nominated if a mutation is present that is covered by the particular test.

Types of Testing

  • Confirmational diagnosis of symptomatic individual.
  • Predictive testing:
    • Predict possible future illness.
    • Predict carrier state in individuals whose children might be at risk.

What mutations can occur?

Missense Mutation

The sun was hot. The man did not get his gat. The hat was old.

Nonsense Mutation

The sun was hot. The man did not old.

Insertion Mutation

The sun was hot. The man did not not get his hat. The hat was old.

Deletion Mutation

The sun was hot. The did not get his hat. The hat was old.

Inversion Mutation

The sun was hot. The get not did man his hat. The hat was old.

Other names used in relation to mutations include point, frameshift, duplication, translocation.

HSP Gene Testing – Prevalence

Tests for  the 3 main genes are available to all Australians at risk of HSP via the Molecular Medicine Laboratory at Concord Hospital, Sydney. These 3 genes represent about half of all HSP incidence.

Spastin (16 exons) SPG4

Atlastin (13 exons) SPG3A

REEP1 (? exons) SGP31

Mutation Discovery by DNA Scanning

  • Spastin & Atlastin

o High Resolution Melt (HRM) – Missense, Nonsense, small insertion, small deletion

o MLPA* – Exon Duplication, Exon Deletion

  • REEP1

o High Resolution Melt (HRM) – Missense, Nonsense, small insertion, small deletion

  • Known mutations in spastin, atlastin, NIPA1

o DNA sequencing

* Multiplex Ligation-dependent Probe Amplification