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Gene & Protein in Disease ABCA12 gene in Harlequin ichthyosis

1. Introduction dead keratinocytes (corneocytes) that are surrounded by
a lipid-rich extracellular matrix, which provides a barrier
Harlequin ichthyosis (HI) is a rare, autosomal recessive function. 5
disorder that manifests at birth with distinctive, severe
skin abnormalities. The hallmark features of HI include In individuals with HI, ABCA12 mutations lead to
hyperkeratotic plaques, a rigid and thickened skin surface, defective lipid transport, disrupting the synthesis of
and deep fissures. These skin changes are not only essential lipids such as ceramides, cholesterol, and fatty
1
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aesthetically distressing but also pose significant functional acids. These lipids are crucial for the formation of the
challenges for affected individuals. The disease is caused lipid bilayer in the stratum corneum. When lipid transport
by mutations in the ABCA12 gene, which encodes a lipid is impaired, the corneocytes do not properly mature
transporter protein integral to maintaining the skin’s or form a stable barrier, resulting in the characteristic
barrier function. Defective lipid transport, a result of these thick, scaly plaques, and fissures seen in HI. The severity
mutations, disrupts the epidermal differentiation process of the disease is influenced by the nature of the ABCA12
and impairs the formation of the stratum corneum, leading mutations. Loss-of-function mutations, such as deletions
to the characteristic features of HI. 2 or nonsense mutations, typically lead to more severe forms
of the disease, while missense mutations may cause milder
Conventionally, HI was associated with a high neonatal presentations. 4
mortality rate due to complications such as dehydration,
infections, and respiratory distress. However, thanks However, it must be noted that not all mutations
3
to advances in neonatal care and early interventions, are created equal. Over 60% of HI-associated ABCA12
survival rates have markedly improved in recent years. mutations are nonsense or frameshift variants (e.g.,
Understanding the genetic basis of HI and the role of p.Arg130*), leading to truncated, non-functional proteins
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ABCA12 has opened the door to innovative treatment and severe phenotypes. In contrast, missense mutations
options, which this paper will explore in detail. (e.g., p.Gly1501Val) may retain partial lipid transport
activity, correlating with milder disease. Structural
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In this review, we delve into the genetic mechanisms modeling predicts that mutations in nucleotide-binding
underlying HI, focusing on ABCA12 mutations and their domains disrupt ATP hydrolysis, essential for lipid
effects on the skin’s structure and function. Moreover, we translocation.
examine how bioinformatics techniques, especially whole-
exome sequencing (WES), contribute to the identification 3. The role of bioinformatics in the study of
of mutations and help establish genotype-phenotype genetic diseases
correlations. We also explore current therapeutic Bioinformatics has become an indispensable tool in
approaches, including topical treatments, systemic the study of genetic diseases, enabling researchers and
therapies, and the emerging possibilities offered by gene clinicians to identify mutations and explore genotype–
therapy and skin-engineering technologies.
phenotype correlations with unprecedented precision.
2. Genetic mechanisms and the role of With advancements in sequencing technologies and
ABCA12 in HI computational tools (Table 1), the field of bioinformatics
has transformed our understanding of rare genetic
Mutations in the ABCA12 gene, located on chromosome disorders such as HI.
2q34, are the primary causal factor of HI. This gene
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encodes the ABCA12 protein, a member of the 3.1. WES and mutation identification
ATP-binding cassette family of transporters. The protein WES has revolutionized the identification of genetic
plays a crucial role in lipid transport, particularly in the mutations in rare disorders such as HI. This technique
synthesis and transfer of lipids to the outermost layer of the focuses on sequencing the protein-coding regions of the
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epidermis, known as the stratum corneum. The stratum genome, which contain the majority of disease-causing
corneum forms a critical barrier against environmental mutations. This approach is both cost-effective and
insults, preventing dehydration and infection. efficient, allowing researchers to pinpoint pathogenic

The pathophysiology of HI can be understood through mutations that would be challenging to identify using
the lens of epidermal differentiation and lipid metabolism. traditional genetic testing methods. 8
The skin is composed of several layers, with the outermost Through WES, researchers can efficiently identify
layer (the stratum corneum) acting as the first-line mutations in the ABCA12 gene, which is responsible for
defense against dehydration, pathogen invasion, and other HI. Identifying the specific mutation(s) in a patient not
environmental threats. The stratum corneum consists of only facilitates accurate diagnosis but also offers insights

Volume 4 Issue 3 (2025) 2 doi: 10.36922/GPD025050009