Page 100 - GPD-4-3

Gene & Protein in Disease ABCA12 gene in Harlequin ichthyosis

pathogenesis as a self-sustaining cycle in which lipidomic residual ABCA12 activity, where inflammation rather than
disruption, innate immune activation, and secondary complete lipid absence may predominate.
barrier dysfunction reinforce one another. Testing this hypothesis will require integrative research
From a systems biology perspective, multi-omics approaches that combine advanced lipidomic profiling
studies in related keratinization disorders such as lamellar of HI skin to distinguish structural from inflammatory
ichthyosis and atopic dermatitis have revealed that lipid lipid species, and single-cell RNA sequencing to delineate
deficiency in the stratum corneum does not merely the composition and activation status of immune cell
compromise the structural barrier but also initiates populations in lesional versus unaffected epidermis. In
inflammatory signaling cascades. 18,19 These pathways, addition, keratinocyte models generated via CRISPR-
often mediated by Toll-like receptors and inflammasomes, Cas9 editing of ABCA12 could be employed to examine
lead to the release of pro-inflammatory cytokines and the cellular response to lipid perturbation and its link to
recruitment of immune cells. Although such mechanisms inflammatory signaling in vitro. Together, these strategies
22
have not been comprehensively characterized in HI, the may uncover new therapeutic targets and support the
clinical presentation–marked by fissured, hyperkeratotic repositioning of existing anti-inflammatory drugs within
skin and recurrent infections–suggests a similar pattern a precision medicine framework for HI. If validated, the
of immune activation. In particular, the profound inflammatory-lipidome axis could represent a paradigm
deficiency of ω-hydroxyacyl sphingosines in HI, essential shift in our understanding of HI, expanding the focus
for acylceramide-mediated barrier formation, may alter beyond structural lipid restoration to include active
keratinocyte stress signaling pathways. This alteration immunomodulation as a core component of treatment. 23
could result in the upregulation of key cytokines, including
interleukin (IL)-1β, IL-36γ, and tumor necrosis factor alpha 6. Challenges and future directions
(TNF-α), which further compromise barrier integrity and Despite the advances in genetic research and treatment
drive chronic inflammation. options, several challenges remain in the management

Supporting this hypothesis, bioinformatic pathway of HI. The disease’s rarity, combined with the complexity
enrichment analyses using KEGG and Reactome databases of ABCA12 mutations, makes it difficult to develop
have identified significant intersections between lipid standardized treatment protocols. The limited number
metabolic pathways and inflammatory signaling cascades of affected individuals globally creates challenges for
in gene networks associated with ABCA12. Genes such as conducting large-scale clinical trials, which are necessary
ALOX12B, ELOVL4, and SMPD1, which are co-expressed to validate emerging therapies. In addition, the high
with ABCA12 during epidermal differentiation, contribute variability in disease severity based on genotype–
not only to the biosynthesis of structural lipids but also to phenotype correlations necessitates highly personalized
the production of lipid-derived inflammatory mediators, treatment plans for each patient, requiring substantial
including prostaglandins and leukotrienes. These resources and multidisciplinary care teams. 4
20
mediators are potent activators of NF-κB and MAPK This is where identification of mutations may play
signaling pathways. This convergence suggests a feedback a key role in the treatment of HI. Advances in mutation
loop in which defective lipid biosynthesis amplifies identification (e.g., WES, NGS) now enable tailored
inflammatory signaling, which in turn further disrupts HI management. For loss-of-function mutations (e.g.,
lipid homeostasis and epidermal function. p.Arg130), early aggressive barrier repair with ceramide-
Clinically, patients with HI frequently display signs dominant emollients (discussed above) may compensate
6,12
of persistent erythema and inflammatory skin changes for absent ABCA12 activity. In contrast, missense
that are only partially responsive to systemic retinoids variants (e.g., p.Gly1501Val) with residual function
and topical corticosteroids. While these treatments are may respond to lower-dose oral retinoids, minimizing
21
16,17
typically employed for their effects on differentiation toxicity. Emerging therapies such as ABCA12-targeted
and keratinization, their anti-inflammatory properties CRISPR (also discussed above) are being prioritized for
19
may also play a significant role. Importantly, targeted severe truncating mutations in preclinical models. This
anti-inflammatory therapies–such as IL-1 inhibitors or mutation-centered paradigm underscores the need for
phospholipase A2 blockers–have not been systematically rapid genetic diagnosis to stratify treatment intensity.
studied in HI, despite their success in treating other However, access to advanced diagnostic tools, such as
inflammatory skin conditions. Under the proposed whole-exome and NGS, can also be limited in resource-
21
inflammatory-lipidome axis framework, such agents may poor settings, further complicating timely and accurate
have therapeutic potential, particularly in individuals with diagnoses. The long-term safety and efficacy of emerging

Volume 4 Issue 3 (2025) 5 doi: 10.36922/GPD025050009