Tay-Sachs disease is caused by a recessively inherited...

Tay-Sachs disease is caused by a recessively inherited mutation in the gene coding for the enzyme hexosaminidase $\mathrm{A}(\mathrm{HEXA}),$ which normally breaks down a lipid called GM2 ganglioside. Accumulation of this lipid in the brain leads to progressive deterioration of the nervous system and death, usually by age $4 .$ HEXA activity in blood serum is 0 to 6 percent in homozygous recessives and 7 to 35 percent in heterozygous carriers, compared with non-carriers (100 percent). The most common mutation in the $H E X A$ gene is an insertion of four base pairs, which presumably leads to a premature stop codon. How would you do genetic screening for carriers of this disease by enzyme testing and by DNA testing? What are the advantages of DNA testing? How would you investigate the premature stop codon hypothesis?

Key Concepts

Investigation of Premature Stop Codon

The premature stop codon hypothesis involves analyzing whether a mutation introduces an early termination signal in the mRNA, leading to a truncated, nonfunctional protein. This can be investigated using methods such as mRNA analysis, in vitro expression studies, and protein assays. Such analyses help confirm if the insertion mutation results in nonsense-mediated decay or production of a defective protein, thereby validating the proposed molecular mechanism behind the disease.

Enzyme Activity Assay

Enzyme activity assays are laboratory tests that measure the level of a specific enzyme in biological samples. In carrier screening, such as for autosomal recessive conditions, these tests quantify enzyme function to detect reduced activity levels that indicate heterozygous or homozygous mutations. They serve as an indirect method of detecting genetic mutations by evaluating their physiological impact on enzyme function.

DNA-based Genetic Testing

DNA-based testing directly assesses an individual’s genetic material to identify specific mutations. Techniques such as PCR and DNA sequencing are used to detect insertions, deletions, or point mutations in target genes. Advantages of DNA testing include high specificity and sensitivity, the ability to detect mutations irrespective of enzyme expression levels, and it can reliably identify carriers even when phenotypic tests are ambiguous.

Transcript

00:01 All right, this question is asking about tasx.

00:03 It's very long, but we're just going to break it down piece by piece and see if we can figure out the answer.

00:09 All right.

00:10 Tasx is a recessive disease.

00:15 That means that in order to have the full -blown disease, you have to have two mutated alleles, one from mom, one from dad.

00:24 All right? and when someone has tasx disease and they have the two mutated alleles, they are not able to produce an enzyme and this enzyme is called hexoaminidias aminidase a abbreviated hexa which i am going to abbreviate the rest of the way because i don't want to say that again and so this hexa enzyme it breaks down a lipid called gm2 ganglia aside and just a side note tasx is a terrible disease um, it usually, uh, if a baby has it, they won't survive past the age of four.

01:14 And it's just really hard to watch them deteriorate and die.

01:18 So it's just a terrible disease.

01:20 And it's all because they don't have this enzyme to break down this right here.

01:24 And then it accumulates in the brain ends up killing them.

01:28 All right.

01:28 So it says that about, uh, this hexa enzyme that's in someone who is homozygous, recessive, which means they have two mutated alleles, they have full -blown tasax, that the enzyme works 0 to 6 % of the time.

01:52 Someone who's heterozygous, which they would have a normal allele and a mutated allele, their enzymes work about 7 to 35 % of the time, and someone who's normal, aka homozygous dominant, their enzymes work 100 % of the time.

02:11 So that is the breakdown of the first part of the question.

02:16 It then asks, how would you screen people and see if they were carriers? so how would you test to find out if they were carriers? and it asks how you would test them in two different ways.

02:32 First, how would you do enzyme testing? well, enzyme testing would be done by taking cells that are not.

02:42 Known to use this enzyme and then testing their function of it...

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