Clinical Genetics and Genomics of Aging by Unknown

Author:Unknown
Language: eng
Format: epub
ISBN: 9783030409555
Publisher: Springer International Publishing

Mutations in Splice Sites and Regulatory Sequences

The most common types of splicing-related mutations that occur are those of cis-acting elements, such as the core consensus sequences (both 5′ and 3′ SS, as well as the BPS) as well as other splicing regulatory sequences [19]. Among these, familial dysautonomia is a rare recessive disorder in the Ashkenazi Jewish population that affects both the autonomous nervous system and the somatic sensory neurons [42]. Caused by a point mutation in intron 20 (T→C) in the IKBKAP gene, that results in the alteration of a 5′ SS weakening the binding of the spliceosome subunit U1, leading to the skipping of exon 20 which results in the introduction of a PTC in exon 21, making the mRNA susceptible to degradation by the NMD pathway [43].

One of the best studied cases of splicing alterations of cis-acting elements that end up being the cause of a pathological condition is spinal muscular atrophy (SMA). SMA is a prevalent recessive disorder associated with infant mortality; more than 90% of all cases of SMA are the result of mutations of the Survival Motor Neuron 1 (SMN1) gene. Humans carry two copies of the SMN gene: SMN1 and SMN2. SMN is required for proper snRNP synthesis, and its absence leads to degeneration of motor neurons, particularly those of the spinal cord. The main difference between the two copies is the fact that in SMN2 exon 7 is predominantly skipped in most tissues. SMN2 codes for SMNΔ 7, a partially functional and unstable protein. Loss of SMN1 leads to a deficit of the SMN protein and the consequent death of motor neurons. SMN2 presents a C→T change at position 6 of exon 7. This single mutation causes two different outcomes: first, the deletion of an ESE, and second, it creates an ESS, which in turn promotes the skipping of exon 7 [44].

Another well-documented case is Duchenne muscular dystrophy (DMD). While genomic deletions of the dystrophin gene cause the most severe forms of DMD, some mild forms of DMD are caused by point mutations that affect the splicing patterns [37]. Particularly, a T→A substitution in exon 31 simultaneously generates an ESS resulting in exon skipping and introduces a PTC [45]. These splicing alterations produce a partially functioning form of the protein, which explains the mild phenotype of the disease.

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