Cell Biology MCAT Practice Question
A 34-year-old woman presents with selective hearing loss and mild intellectual disability. Genetic testing reveals a heterozygous loss-of-function mutation in KAT6A, which encodes a histone acetyltransferase (HAT) subunit of a transcriptional coactivator complex. Western blot analysis shows that the mutant protein is expressed at normal levels and the coactivator complex assembles normally. However, the overall HAT enzymatic activity of the complex is reduced to approximately 50% of wildtype levels. Gene expression analysis in patient fibroblasts shows significantly reduced transcription of KAT6A target genes compared to controls. The patient's parents have normal hearing and no neurological symptoms. Which of the following best explains why the heterozygous mutation produces a clinically significant phenotype despite 50% residual HAT activity?
Answer choices
- AThe mutant HAT protein assembles into coactivator complexes alongside wildtype subunits, creating catalytically impaired hetero-oligomeric complexes that poison the overall activity of the complex below the level of simple haploinsufficiencyCorrect answer
- BIncreased histone deacetylase (HDAC) activity compensates for reduced HAT activity, leading to net loss of histone acetylation at target gene promoters
- CThe tissue-specific transcription factors required for KAT6A target gene expression preferentially interact with the mutant coactivator complexes, preventing formation of functional transcriptional machinery
- DThe 50% reduction in HAT activity is sufficient to initiate transcription but not maintain sustained mRNA synthesis, resulting in degradation of incomplete transcripts
- EThe mutant HAT protein directly inhibits DNA binding by competing with the DNA-binding domain of associated transcription factors
- FHeterozygosity for the HAT mutation reduces acetylation of histone H3 lysine 27 specifically, which prevents recruitment of RNA Polymerase II to target promoters
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