A hereditary disease is inherited as an autosomal recessive trait1. The wild-type allele of the disease gene produces a mature mRNA that is 1250 nucleotides (nt) long. Molecular analysis shows that the mature mRNA consists of four exons that measure 400 nt (exon 1), 320 nt (exon 2), 230 nt (exon 3), and 300 nt (exon 4). A mother and father with two healthy children and two children with the disease have northern blot analysis performed in a medical genetics laboratory. The results of the northern blot for each family member are shown here. Based on your analysis, what is the most likely molecular abnormality causing the disease allele?

Verified step by step guidance

1. Step 1: Understand the inheritance pattern. The problem states that the disease is inherited as an autosomal recessive trait. This means that affected individuals must inherit two copies of the disease allele (one from each parent), while carriers have one wild-type allele and one disease allele.
2. Step 2: Analyze the wild-type mRNA structure. The mature mRNA is 1250 nucleotides long and consists of four exons: 400 nt (exon 1), 320 nt (exon 2), 230 nt (exon 3), and 300 nt (exon 4). The sum of these exon lengths matches the total length of the mature mRNA, confirming proper splicing in the wild-type allele.
3. Step 3: Examine the northern blot results. Northern blot analysis detects RNA molecules and provides information about their size and abundance. Compare the mRNA sizes observed in the affected children, healthy children, and parents to identify any abnormalities in the disease allele.
4. Step 4: Hypothesize the molecular abnormality. If the northern blot shows an mRNA size different from 1250 nt in affected individuals, this suggests a splicing defect, deletion, or insertion in the disease allele. For example, if an exon is missing or improperly spliced, the mRNA length would be shorter than expected.
5. Step 5: Correlate findings with the inheritance pattern. Since the disease is autosomal recessive, both affected children must have inherited the disease allele from each parent. Use the northern blot results to confirm whether the parents are carriers (one wild-type and one disease allele) and whether the healthy children inherited at least one wild-type allele.

Key Concepts

Autosomal Recessive Inheritance

Autosomal recessive inheritance refers to a pattern where two copies of a mutated gene, one from each parent, are necessary for an individual to express a hereditary disease. In this case, healthy parents can be carriers of the mutation without showing symptoms, but they can pass the mutated allele to their offspring, leading to the disease in children when both alleles are recessive.

Mature mRNA and Exons

Mature mRNA is the final product of gene expression after transcription and splicing, which includes only the coding regions called exons. In this scenario, the mature mRNA is composed of four exons of varying lengths, indicating that the gene undergoes splicing to remove non-coding regions (introns) and produce a functional mRNA that can be translated into a protein.

Northern Blot Analysis

Northern blot analysis is a technique used to detect specific RNA sequences in a sample. It involves the separation of RNA by gel electrophoresis, transfer to a membrane, and hybridization with labeled probes. This method can reveal the presence, size, and abundance of mRNA, helping to identify molecular abnormalities such as deletions or mutations that may lead to disease.