Integrating genomic structural equation modeling and experimental validation to unravel the genetic basis of male genital lichen sclerosus.

Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous metalloenzymes found in vertebrates and invertebrates, mainly containing zinc as a metal ion. The fundamental role of CAs is the reversible hydration of carbon dioxide to bicarbonate and hydrogen ions in a reaction CO + HO ⇋ HCO + H. The biological significance of CAs mainly lies in their involvement in various biological processes, namely photosynthetic reactions, acidification within renal tubules, respiratory pathways, and bone resorption. The CAs belong to evolutionarily eight different gene families and are identified by Greek letters: α, β, γ, δ, ζ, η, θ, and ι. The animal kingdom contains only CAs belonging to the -α class, and humans are known to contain 16 α-CAs. Among the α-CA, thirteen CAs, namely, CA I, II, III, IV, VA, VB, VI, VII, IX, XII, XIII, XIV, and XV, are catalytically active. In the catalytically active CAs, zinc in the active site is coordinated by three histidine residues essential for the enzyme’s catalytic activity. The catalytic activity of the CAs is necessary for maintaining the overall biological reactions associated with the modulation of various biological pathways involved in the healthy functioning of the tissues and organs. The remaining three CAs are catalytically inactive and are known as carbonic anhydrase-related proteins (CARPs). The catalytic inactivity of the CARPs is due to the absence of one or more of the three histidine residues required for the coordination of the zinc atom in the activity site. Studies related to CARPs mainly include gene expression studies conducted using western blot, RT-PCR techniques, and immunohistochemistry within the brain tissues of humans, mice, and zebrafish. These studies have shown that CARPs are predominantly expressed in the brain and central nervous system. Among the CARPs, CARP VIII is predominantly expressed in the cerebellar region of the brain and, more specifically, in the Purkinje cells, whereas CARP X and CARP XI are expressed in all parts of the brain. The expression studies on the CARPs showed that these proteins are localized along the brain tissues, denoting the differential expression of CA VIII, X, and XI within neural tissues, and hence could be potentially connected to the modulation of proteins through interaction with other proteins associated with the development of brain tissues and contribute to neural functioning, hence leading to the proper functioning of neurological health among humans. Studies have shown that the mutations in the gene resulted in neurological disorders like ataxia and gait disorders in mice. The spontaneously occurring mutation in the gene in the members of Saudi Arabian and Iraqi led to mental retardation and ataxia and quadrupedal gait, respectively. MRI analyses of affected family members revealed reduced cerebellar volume, suggesting that mutations in the gene contribute to cerebellar abnormalities that impair motor coordination and cognitive development. In addition, knockout and knockdown studies in zebrafish showed that these proteins are crucial for brain development, and defects in these proteins lead to ataxia and motor coordination defects. Similarly, studies conducted on cancer cell lines and malignant tissues provided the inference that CARP VIII, CARP X, and CARP XI were more involved in the cancer development pathways, which were mainly found to localize within gastrointestinal tracts and pulmonary tissues. Moreover, CA VIII has also been found to be involved in various carcinogenic conditions, which are mostly localized within fetal cells during their development and also found within colon and pulmonary tissues, leading to cancerous development within them. Similarly, research conducted on CA X and XI also produced similar results, pointing to their potential connections among cancer development pathways and involvement within the neurological functioning of human beings, which, during events of malfunction, led to the development of disorders that affected the neurological tissues and also led to cancer along multiple organs. Recent CA drug-discovery studies further demonstrate the therapeutic relevance of targeting CA isoforms in cancer and neurological disease-associated contexts. Sulfonamide and triazole-based hCA inhibitors have been designed against several human CA isoforms, including the tumor-associated hCA IX and hCA XII, with studies integrating enzyme inhibition, anticancer cytotoxicity, and molecular docking analyses. Similar structure-guided strategies have also been applied to naphthoquinone–thiazole hybrids, thiosemicarbazone derivatives, and dual hCA/acetylcholinesterase inhibitors, highlighting the relevance of CA modulation in neurodegenerative, glaucoma-related, and cancer-associated pharmacological frameworks. In addition, tail-approach-based inhibitor design has been used to improve isoform selectivity across hCA I, II, IX, and XII. These recent advances provide a strong rationale for integrati