Explaining types and examples of inborn RNA transcription errors

1. Inborn Errors of nuclear RNA processing
 Pre-mRNA splicing is an essential process in
eukaryotic cells during which, noncoding (intronic)
sequences are removed and coding (exonic)
sequences are joined together to generate functional
mRNA. This is catalyzed by spliceosome.
 The most critical step of a splicing reaction is the
accurate determination of the 5′ and 3′ splice sites
(5′ss and 3′ss) that mark the beginning and end of
an intron, respectively.
 Splicing-mutations may lead to abnormal gene
expression and as a result, various human diseases
arise.
Figure showing splicing of introns with the help of
Spliceosome.

2. Types of RNA transcription mutations
 These can be classified as follows:
A. Splice Site Mutations:
These include point mutations in splice sites that may cause diseases like-
Congenital Adrenal Hyperplasia (CAH), Fragile X Syndrome (FXS), etc.
B. Splice Factor Mutations:
These involve the mutation of genes encoding for cell type-specific splicing factors
and may lead to diseases like- Spinal Muscular Atrophy (SMA), Amyotrophic lateral
sclerosis (ALS), etc.

3. (A) Splice Site Mutation
 Congenital adrenal hyperplasia (CAH)
 It is an autosomal recessive disorder that affect
the adrenal glands.
 Caused due to point mutation in the splice site for the
second intron of CYP21 gene, that encodes for enzyme 21-
steroid hydroxylase. The resulting enzyme is ineffective.
 Deficiency of 21-hydroxylase leads to excess amounts of
testosterone (adrenal adrogens) being produced by the
adrenal glands.
 Female with CAH are phenotypically masculinized.
*CYP21 (cytochrome P450
family 21)

4.  Fragile X syndrome (FXS)
 FXS is caused by the absence of an intracellular RNA binding protein, Fragile-X Mental Retardation
Protein (FMRP).
 FMR1 is the gene located on the X chromosome that produces FMRP needed for proper cell function.
 Mutation in FMR1 deregulates dendritic signaling pathways in the brain.
 The main recurrent mutagenic mechanism behind this is the CGG-repeat expansion in the 5′-
untranslated region (5′UTR) of FMR1, inducing abnormal methylation of this region followed by
transcriptional silencing.

5. (B) Splice Factor Mutation
 Spinal Muscular Atrophy (SMA)
 Humans carry two near identical copies of the Survival Motor
Neuron gene: SMN1 and SMN2.
 Both SMN genes code for multifunction SMN protein,
essential for maintenance of motor neurons.
 Deletion or Mutation of SMN1 due to splicing out of exon 7
leads to spinal muscular atrophy (SMA), a major genetic
disease of children and infants.
 Although nearly identical, SMN2 does not compensate for the
loss of SMN1.

6.  Amyotrophic Lateral Sclerosis (ALS)/ Lou Gehrig’s Disease
 Amyotrophic lateral sclerosis (ALS) is a type of progressive, motor neuron
disease and is associated with aberrant expression and/or localization of SMN.
 Causes dysfunction in the nerves which control muscle movement.
 Two main types:
a) Sporadic ALS: Random, accounts for 90-95% of cases. There is no clear risk
factor or cause.
b) Familial ALS: Inherited, accounts for 5-10% of cases. The child of a person
with ALS will have a 50 percent chance of developing the condition.
Stephen Hawking

7. References
Inborn Errors of nuclear RNA processing (Ankita Das)
• Cartegni L, Hastings ML, Calarco JA, de Stanchina E, Krainer AR. Determinants of exon 7 splicing in the
spinal muscular atrophy genes, SMN1 and SMN2. Am J Hum Genet. 2006;78(1):63–
77. https://doi.org/10.1086/498853.
• Singh Ravindra N., Singh Natalia N. “Mechanism of Splicing Regulation of Spinal Muscular Atrophy
Genes”. 20: 31–61. doi: 10.1007/978-3-319-89689-2_2
• Angélique Quartier et al. “Intragenic FMR1 disease-causing variants: a significant mutational mechanism
leading to Fragile-X syndrome”. European Journal of Human Genetics (2017) 25, 423–431;
doi:10.1038/ejhg.2016.204.
• https://www.medicalnewstoday.com/articles/281472