The isoenzyme hexosaminidase A (HEXA), composed of subunits and , breaks down mo

Question

The isoenzyme hexosaminidase A (HEXA), composed of subunits and , breaks down molecules containing terminal N-acetyl hexosamines. Tay-Sachs disease is caused by a recessively inherited mutation in the gene coding for the subunit, which is the subunit that hydrolyzes the lipid GM2 ganglioside. Accumulation of this lipid in the brain leads to progressive deterioration of the nervous system and death, usually by age 4. A child born homozygous for the loss-of-function subunit allele nevertheless does not develop Tay-Sachs disease. Sequence analysis of the subunit alleles reveals that one allele has a mutation that makes it able to hydrolyze GM2 ganglioside. The subunit mutation is a _______-of-function mutation, which is most likely _______.

gain; dominant
gain; recessive
loss; dominant
loss; recessive
loss; intermediately dominant

Explanation / Answer

Answer: gain; recessive

The GM2 gangliosidoses are caused by mutations in the genes encoding the - (Tay-Sachs) or - (Sandhoff) subunits of heterodimeric -hexosaminidase A (Hex A), or the GM2 activator protein (AB variant), a substrate-specific co-factor for Hex A. Although the active site associated with the hydrolysis of GM2 ganglioside, as well as part of the binding site for the ganglioside-activator complex, is associated with the -subunit, elements of the -subunit are also involved. Missense mutations in these genes normally result in the mutant protein being retained in the endoplasmic reticulum and degraded. The mutations associated with the B1-variant of Tay-Sachs are rare exceptions that directly affect residues in the -active site.

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