The most common diseases with genetic origin like muscular dystrophy seem to originate from issues with the primary structure of the DNA itself. Also it seems to be somewhat controversial as to whether alternate splicing of a single gene is actually a functional process, rather than biomolecular noise. In that context, do we know of any disease where the primary structure of a certain gene is normal, but the end products are not.


1 Answer 1


Misconceptions etc. in the Question

There are several misconceptions and erroneous or unclear statements in this question, which first need to be dealt with.

  1. Whether or not muscular dystrophy is a common genetic disease, depends on whether you think 1 in 3500–6000 male births is common. I would term it ‘well-known’.
  2. It is not controversial whether alternative splicing of a single gene is a ‘functional process’ (whatever that may mean). One well studied and unequivocal example is in sex determination in Drosophila melanogaster — see the Wikipedia entry for Alternative splicing and my own answer to a question on this list.
  3. Alternative splicing of a gene involves splicing sites that may or may not be part of the spliced transcript (the mature mRNA). The title of the question asks for diseases of malfunction of alternative splicing, whereas the body of the question refers to a normal “primary structure” for the gene. I shall assume that examples in which there are mutations in splice sites that are in introns — and hence not in the mRNA or the protein — satisfy the criterion. However enhancer mutations will also be considered.
  4. The reference to “post-translational changes in the genome” in the title does not relate to the rest of the question or make much sense to me. I shall ignore it.


There are several reviews on this topic, but I shall confine myself to the first that I found from an internet search — one entitled Splicing mutations in human genetic disorders: examples, detection, and confirmation by Abramowicz and Gos in J Appl Genet. 2018; 59(3): 253–268. Table 1 of that paper list examples of genetic diseases extending to three pages (perhaps easier to read online horizontally here) which include the following:

  • congenital cataract
  • Neurofibromatosis type 1
  • Ehlers-Danlos syndrome
  • Succinyl-CoA:3-ketoacid CoA transferase deficiency
  • Becker muscular dystrophy
  • Familial dysautonomia
  • Cystic fibrosis
  • Androgen insensitivity syndrome
  • Fabry disease

The mutations causing the aberrant splicing include mutations in the donor or acceptor splice site, intron variants, and exonic and intronic splicing enhancers. The results of these mutations include exon skipping, cryptic exon inclusion, and alteration of the relative frequency of occurrence of different spliced transcripts.

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    $\begingroup$ +1. Maybe you could also find examples of diseases caused by splicing regulators, so that primary sequences of targets may be completely normal including splicing sites. $\endgroup$
    – KaPy3141
    Commented Jan 9, 2023 at 16:56
  • $\begingroup$ @KaPy3141 — I agree, that would be good. Now finding the time... $\endgroup$
    – David
    Commented Jan 9, 2023 at 18:47

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