Mutations and Inborn Errors of Metabolism (1C) - Bio & Biochem

1. Which mutation type is most likely to produce a premature stop codon: missense or nonsense?

   Nonsense. Nonsense mutations directly change a sense codon to a stop codon, unlike missense which alters amino acids without stopping translation.

2. What is the probability that a child is a carrier if both parents are carriers for an autosomal recessive disorder?

   $\frac{1}{2}$. With both parents as carriers, children have a 50% chance of being heterozygous carriers per Mendelian inheritance.

3. Identify the expected phenotype of a heterozygous carrier for an autosomal recessive IEM.

   Typically asymptomatic (one functional allele is usually sufficient). In autosomal recessive IEMs, heterozygotes usually have sufficient enzyme activity from one allele to remain unaffected.

4. What is the definition of a silent (synonymous) mutation?

   A nucleotide change that does not alter the amino acid. Silent mutations occur due to the degeneracy of the genetic code, where multiple codons specify the same amino acid.

5. What is the definition of a missense mutation?

   A nucleotide change that substitutes one amino acid for another. Missense mutations change the codon to one that codes for a different amino acid, potentially altering protein function.

6. What is the definition of variable expressivity?

   Differences in severity or features among individuals with same genotype. Variable expressivity reflects how modifiers and environment cause phenotypic variation in individuals sharing the same mutation.

7. What is the definition of a point mutation?

   A single-nucleotide change at a specific DNA position. Point mutations involve a substitution, insertion, or deletion of a single nucleotide, altering the DNA sequence at one specific position.

8. Which inheritance pattern is most common for inborn errors of metabolism?

   Autosomal recessive. Most inborn errors of metabolism follow autosomal recessive inheritance due to loss-of-function mutations in enzyme-coding genes.

9. What is the definition of an in-frame insertion or deletion?

   Insertion or deletion in multiples of $3$ that preserves reading frame. In-frame mutations add or remove whole codons, maintaining the original reading frame and downstream sequence integrity.

10. What is the definition of a promoter (regulatory) mutation?

    A DNA change that alters transcription factor binding and gene expression. Promoter mutations modify regulatory regions, influencing the rate of transcription initiation and overall gene expression levels.

11. What is the definition of a frameshift mutation?

    Insertion or deletion not in multiples of $3$ that shifts reading frame. Frameshift mutations disrupt the triplet reading frame of codons, resulting in altered amino acid sequences downstream.

12. What is the probability that two carrier parents have an affected child for an autosomal recessive disorder?

    $ $ $\frac{1}{4}$. For autosomal recessive disorders, each child has a 25% chance of inheriting two mutant alleles from carrier parents.

13. If a coding sequence loses $2$ nucleotides, what mutation class best describes the effect on translation?

    Frameshift mutation. Loss of 2 nucleotides shifts the reading frame, as it is not a multiple of 3, altering all subsequent codons.

14. What is the definition of haploinsufficiency?

    One functional allele is insufficient for normal phenotype. Haploinsufficiency occurs when a single copy of the gene fails to produce enough product for normal function, leading to dominant inheritance.

15. What is the definition of a dominant-negative mutation?

    Mutant protein interferes with the function of the normal protein. Dominant-negative mutations produce defective proteins that inhibit wild-type counterparts, often in multimeric complexes.

16. What is the typical biochemical mechanism of many inborn errors of metabolism?

    Enzyme deficiency causing substrate buildup and product deficiency. Inborn errors often stem from mutations causing enzyme deficiencies, disrupting metabolic pathways with substrate accumulation and product shortage.

17. What is the definition of a splice-site mutation?

    A mutation that disrupts intron removal or exon joining in pre-mRNA. Splice-site mutations affect consensus sequences at intron-exon boundaries, impairing proper mRNA splicing.

18. What is the definition of a gain-of-function mutation?

    A mutation that increases activity or creates a new function. Gain-of-function mutations enhance or confer novel activities, frequently resulting in dominant phenotypes.

19. Which mutation preserves the reading frame: deletion of $1$ nucleotide or deletion of $3$ nucleotides?

    Deletion of $3$ nucleotides. Deletion of 3 nucleotides removes one codon entirely, preserving the downstream reading frame unlike single nucleotide deletions.

20. What is the typical protein-level effect of a frameshift early in a coding region?

    Truncated, nonfunctional protein due to altered downstream sequence. Early frameshifts often introduce premature stop codons, producing shortened proteins that lack functionality.

21. What is the definition of penetrance in human genetics?

    The fraction of individuals with a genotype who express the phenotype. Penetrance measures the proportion of genotype carriers showing the expected phenotype, influenced by genetic and environmental factors.

22. What is heteroplasmy in mitochondrial genetics?

    A mixture of normal and mutant mtDNA within a cell or individual. Heteroplasmy arises from random segregation of mutant and wild-type mtDNA during cell division, affecting disease manifestation.

23. What is the definition of a nonsense mutation?

    A mutation that converts a codon into a premature stop codon. Nonsense mutations introduce a stop codon prematurely, leading to truncated proteins.

24. What is the definition of a loss-of-function mutation?

    A mutation that reduces or abolishes normal gene product activity. Loss-of-function mutations impair gene product efficacy, often leading to recessive phenotypes in diploid organisms.

25. What is the key inheritance feature of mitochondrial DNA mutations?

    Maternal inheritance. Mitochondrial DNA is inherited solely from the mother, as sperm contribute negligible mitochondria to the zygote.

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