Exploring HOXA2 Mutation: Genetic Cause of Microtia-Anotia Development

This essay delves into the genetic underpinnings of Microtia-Anotia, a spectrum of congenital anomalies affecting the auricle. It focuses on the hypothesis that a mutation in the HOXA2 gene leads to the development of this condition. The essay discusses the normal function of the HOXA2 gene, which encodes the homeobox protein Hox-A2 and plays a crucial role in embryonic development, particularly in hindbrain segmentation and facial development. It regulates the Wnt-signaling pathway, essential for inner and outer ear development. The disruption of this gene due to factors like anemia, medication consumption, or gestosis during pregnancy, leads to a missense mutation in HOXA2, down-regulating Wnt signaling. This results in abnormal outer ear development, hearing loss, and in severe cases, the complete absence of the ear (Anotia). The essay also touches upon surgical reconstruction options available for affected individuals, typically performed between 4 to 10 years of age.

Running head: MICROTIA- ANOTIA
MICROTIA- ANOTIA
Name of the student:
Name of the university:
Author note

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Introduction:
Microtia-anotia is considered as a spectrum of congenital anomalies of the auricle which
results in mild structural abnormalities and severe cases, the complete absence of the pinna. The
Microtia/ Anotia may occur only in one ear or both ears and these deformities will result in
conductive hearing loss, deafness (Billings et al. 2016). As discussed by Wang et al. (2017),
majority of the individuals experienced Microtia/ Anotia due to genetic defects and
approximately 20 % to 40% of the infants with Microtia/ Anotia exhibit additional defects which
further developed into the syndrome. Hence, this paper aims to provide ONE genetic cause, the
molecular function of the gene, through the cellular effect of the protein, to the role in the
developing tissue, and how disruption of this gene leads to the defect in the following
paragraphs.
Hypothesis: a mutation in the gene HOXA2 leads to the development of microtia/ anotia.
Discussion:
Genetic cause and normal function:
Microtia is a genetic condition affecting the external ears and presents clinically along a
wide spectrum where mutation of HOXA2 is considered as the reason behind the development of
the disease (Stoll et al. 2016). In human, HOXA2 encode for homeobox protein Hox-A2 and
found in the cluster named A, B, C and D on four separate chromosomes. Expression of these
genes is completely or partially regulate during the embryonic development of humans. This
gene is part of A cluster on chromosome 7 and it encodes DNA binding transcription factor that
further regulates genetic expression, morphogenesis, and differentiation. During the embryonic
process, the homeobox protein Hox-A2 involve in the placement of the hindbrain segment in the

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proper location. Apart from hindbrain development and anteroposterior patterning of embryo, it
controls the embryonic development of the lower and middle part of the face and middle ear
(Gendron, Schwentker and van Aalst 2016). Geng et al. (2017), suggested that HoxA2 regulates
the Wnt-signaling pathway which further controls the embryonic development of the inner ear
since this pathway controls the cell proliferation, cochlear, polar orientation of stereociliary
bundles. The gene also controls the embryonic development of the outer ear in humans and
similar molecular mechanism also exhibited in mouse models. Hence, many researchers
suggested that the tissue-specific activation of canonical WntB caternine signalling regulated by
HoxA2 highly observed. In the later developmental stage, canonical Wnt -B- catenin signalling
remain highly active in the outer ears. Hence, HoxA2 plays a crucial role in embryonic
development of ear amongst humans and mice.
Development of microtia/ anotia due to dysfunction of the genes:
The critical contribution of the HoxA2 gene in embryonic development of the auditory-
system has already been shown in mouse models, even in human which results in Microtia/
Anotia. As discussed by Wang et al. (2017), while the exact underlying reason behind the
development of Microtia/ Anotia is poorly understood, the researchers suggested that major
contributing factors behind the development of disease include gestosis or expanded toxemia,
anemia and consumption of certain medications such as isotretinoin. These conditions are highly
applicable for pregnant mothers, especially when mothers are 18 weeks or more than 18 weeks
pregnant till 24 weeks since during this period, embryonic development of ears observed and
foetus can hear sounds. However, gestational diabetes, underweight are also contributing factors
that induce mutation (Gendron, Schwentker and van Aalst 2016). Nuñez-Castruita and López-
Serna (2018) suggested that due to risk factors discussed above, a missense mutation in the

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HOXA2 ( homeobox gene) induce bilateral Microtia / Anotia. On the other hand, along with
autosomal-dominant or -the recessive inheritance of Microtia, chromosomal abnormalities are
observed such as four frequently observed trisomies in chromosome number 18, 13, 21 and 88.
Considering the cellular mechanism, the mutation in HoxA2 impacts the Wnt–β-catenin
signaling and reduced the over activation of the Wnt–β-catenin signaling in outer ear outgrowth
amongst the infants. Interestingly, it was observed that due to dysfunction of Wnt–β-catenin
signaling in the outer ear due to missense mutation, outer ear early develops abnormally where
mesenchymal inactivation of β-catenin in the branchial arches observed (Geng et al. 2017). Data
obtained from subsequent DNA sequence analysis of HOXA2 suggested that all HOX genes
share 60 amino acid domain called homeodomain and mutation observed in a highly conserved
amino acid which results in inactivation of Wnt signalling pathway (Geng et al. 2017). In the
model of the mutant homeodomain, the position of the mutant lysine side chain becomes distant
from the nearby phosphate group which in turn induce a loss of hydrogen bond and negatively
impacted the DNA binding activity. In the case of patients, the common abnormality is hearing
loss caused by insufficient conduction of sound to inner ear since sound cannot travel to the inner
ear due to the absence of no ear, no eardrum and the ear bones. In Microtia when genetic
malfunction becomes severe during the embryonic developmental stage, the absence of total ear
or Anotia observed. Anotia is the last stage or the fourth stage of Microtia developed during the
first few weeks of pregnancy where both of the ears become affected (Billings et al. 2016). On
the other hand, Piceci et al. (2017), suggested that similar features also observed in the case of
infants with autosomal dominant non-syndromic microtia. The non-syndromic microtia, non-
sense mutation of the gene HOXA2 also observed which further contributed to distinctive ear
morphology. Since it is visible during birth, a CT scan of the ear of the infants can provide a

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detailed picture of the ear. The surgery of the ear can reconstruct the external ear where the time
of the surgery depending on the severity of the disease. Surgeries usually perform at 4 to 10
years of age.
Conclusion:
On a concluding note, it can be said that Microtia/ Anotia spectrum of congenital anomalies of
the auricle which results in mild structural abnormalities to complete absence of the ear. The
researchers hypothesized that mutation in the gene HOXA2 leads to the development of
microtia/ Anotia. HOXA2 is a homeobox protein that acts as a transcriptional factor during
embryonic development and controls the Wnt signaling pathway. However, due to risk factors
such as anemia, consumption of medication gestosis, a missense mutation in HOXA2 observed
which down-regulate Wnt signalling which results in absence of ear and hearing loss. Surgeries
within 4 to 10 years can reconstruct the ear.

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References:
Anthwal, N., & Thompson, H. (2016). The development of the mammalian outer and middle
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Billings, K. R., Qureshi, H., Gouveia, C., Ittner, C., & Hoff, S. R. (2016). Management of
hearing loss and the normal ear in cases of unilateral microtia with aural atresia. The
Laryngoscope, 126(6), 1470-1474.
Gendron, C., Schwentker, A. and van Aalst, J.A., 2016. Genetic advances in the understanding of
Microtia. Journal of pediatric genetics, 5(04), pp.189-197.
Geng, R., Noda, T., Mulvaney, J.F., Lin, V.Y., Edge, A.S. and Dabdoub, A., 2016.
Comprehensive expression of Wnt signaling pathway genes during development and maturation
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Nuñez-Castruita, A. and López-Serna, N., 2018. Low-set ears and associated anomalies in
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Stoll, C., Alembik, Y., Dott, B. and Roth, M.P., 2016. Associated anomalies in cases with anotia
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