Discuss the inheritance, molecular and biochemical defects underlying the clinical features associated with Ataxia Telangiectasia
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BIOL253 (BIOL253)
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Lancaster University (LU)
This essay discusses the inheritance, and molecular and biochemical defects underlying the clinical features associated with the genetic disease Ataxia Telangiectasia. It includes the physiological roles of the ATM protein and implications of mutation within the ATM gene, methods of diagnosis, and...
Discuss the Inheritance, Molecular and Biochemical Defects
Underlying the Clinical Features Associated with Ataxia-
Telangiectasia
Background
Ataxia-telangiectasia (A-T) is a progressive,
neurodegenerative genetic disorder caused by mutations
in a single gene called ‘Ataxia Telangiectasia Mutated’
(ATM), and generally has onset in early childhood. The
clinical picture is characterized by the two main hallmarks
of A-T, which as suggested by its name are: cerebellar
ataxia; referring to a lack of fine control of voluntary
movements, and telangiectasia; the widening of blood
vessels near the surface of the skin or the eyes (as Figure 1: Image showing ocular
shown in Figure 1). Other common features of A-T telangiectasia, a signature
include a predisposition to infections and malignancies, characteristic of A-T, in which
particularly lymphomas and leukaemia’s. Despite the first blood vessels appear red and
description of A-T being made over 90 years ago by spider-like.
Syllaba and Henner (1926), based on their observations
of three Czech siblings, many questions regarding its Source: Knoch et al. (2012)
pathogenesis remain unanswered due to the rarity of the
condition making it challenging to evaluate. Presently, there is still no specific treatment
available for A-T (Perlman et al., 2011). This expresses an urgency for more research on the
molecular processes underlying this debilitating disorder, which could fast-forward the
development of relevant therapeutic strategies. Here, this essay discusses the inheritance of
A-T and the main types of mutations occurring within ATM which compromise the
physiological functions of the protein it encodes. It will conclude with the current methods of
diagnosis and treatment.
Pattern of Inheritance
A-T is inherited in an autosomal recessive manner, occurring when an individual
receives an abnormal ATM gene from both parents. If a mutation is present in only one copy
of the gene, then these heterozygous individuals will become asymptomatic carriers for the
disease (Lohmann et al., 2015). Therefore, when two carriers produce offspring, each child
has a 25% chance of inheriting the two mutated ATM gene copies, becoming homozygous
and affected. This recessive nature of inheritance is concordant with the rarity of the
disorder, with the worldwide prevalence of A-T estimated to be between 1 in 40,000-100,000
live births, affecting males and females equally (Teive et al., 2018). Likewise, there has been
no evidence to suggest that inheritance is more common in different racial or ethnic groups,
aside from in communities with high consanguinity rates. The closer the biological
relationship between parents, the greater the risk of the offspring inheriting one or more
detrimental copies of ATM, as depicted in the pedigree chart of a consanguineous family in
Figure 2 (Hamamy, 2012).
, Figure 2: Pedigree of a family illustrating the
inheritance of A-T, and that consanguinity
increases the likelihood of this happening
due to its autosomal recessive mode of
inheritance
The ATM gene mutation is indicated by a
dotted or filled symbol in the case of
heterozygosity or homozygosity, respectfully.
Carrier Carrier In this diagram, whereby a healthy, carrier
mother is in a relationship with her first
cousin (also a carrier), 50% of her children
were affected by A-T. This is 25% more than
typically expected in a non-consanguineous
relationship. The other 50% of her children
were also carriers.
Carrier Affected Affected Carrier
Adapted from Kuznetsova et al. (2017)
Physiological Roles of ATM protein
The mutated gene responsible for A-T, ATM, is located on the long arm of
chromosome 11 (11q22.3). It consists of 69 exons which span across a genomic region of
approximately 150kb and encodes a protein of the same name. (Asmari et al., 2020). ATM is
a 370kDa serine/threonine protein kinase, belonging to the family of phosphatidylinositol-3-
kinases, and comprises of 3,056 amino acids. In healthy cells, ATM exists as an inactive
dimer and predominantly resides in the nucleus. However, in the presence of DNA double-
strand breaks (DSBs) which, for example, could be induced by ionizing radiation or reactive
oxygen species (ROS), ATM is rapidly converted to its active monomer form (Guleria and
Chandna, 2016). For this to happen, the site of damage is first recognised by the Mre11-
Rad5-NBS1 (MRN) complex. ATM interacts with the C-terminal domain of NBS1, so that it
can be recruited and bound to the ends of the DSBs. Once bound, its autophosphorylation
stimulates its kinase activity, enabling it to phosphorylate other proteins. ATM can then
initiate several signalling pathways that are responsive to such genotoxic stress, some of
which can be seen in Figure 3 (Ambrose and Gatti, 2013).
Two of the most notable substrates of ATM are the checkpoint kinases CHK1 and
CHK2, which contribute to cell cycle arrest at the G1/S and G2/M transitions, respectfully.
This level of control is important to allow time for DNA damage repair before the cell cycle is
continued, thus preventing the propagation of deleterious mutations to progeny cells.
Meanwhile, ATM is involved in triggering DSB end resection to produce single-stranded DNA
overhangs for homologous recombination repair to take place (Balmus et al., 2019). Another
target of ATM is the transcription factor p53 which, once phosphorylated, promotes the
expression of several genes required for inducing apoptosis. This process of programmed
cell death is vital to remove cells with damage that is beyond repair (Stracker et al., 2013).
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