KLICK Syndrome Linked to a POMP Mutation Has Features Suggestive of an Autoinflammatory Keratinization Disease

Abstract

Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is a rare autosomal recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic plaques, ichthyosiform scaling, circular constrictions around the fingers, and numerous papules distributed linearly in the arm folds and on the wrists. Histologically, the affected skin shows hypertrophy and hyperplasia of the spinous, granular, and horny epidermal layers with mild infiltration of inflammatory cells in the upper dermis. There are 14 patients with KLICK syndrome described in the literature, and they all carry the same nucleotide deletion. Proteasome maturation protein (POMP), encoded by POMP, is an ubiquitously expressed protein that functions as a chaperone for proteasome maturation. KLICK syndrome is caused by a reduction in POMP levels that leads to proteasome insufficiency in differentiating keratinocytes. It is noteworthy that POMP is also known to be the causative gene for proteasome-associated autoinflammatory syndrome-2 (PRAAS2). It is considered that the disrupted proteasome assembly caused by the POMP mutation might lead to both skin inflammation and then hyperkeratosis in KLICK syndrome. Inflammation caused by the hyperactivation of innate immunity occasionally leads to inflammatory diseases of the skin, recently denoted as autoinflammatory keratinization diseases (AiKDs). We propose that KLICK syndrome caused by the specific 1-bp nucleotide deletion mutation in the regulatory region of POMP might be in a spectrum of proteasome-associated phenotypes.

Human filaggrin monomer does not seem to be a proteasome target

“…It has recently been suggested to be an autoinflammatory keratinization disease. 9 Patient's epidermis shows hyperkeratosis, parakeratosis and hypergranulosis associated with enlarged and abnormally shaped keratohyalin granules together with abnormal distribution of filaggrin in the Stratum granulosum (absence) and Stratum corneum (broader detection). 10 Altogether, this suggests that the proteasome is involved in the processing of filaggrin.…”

“…KLICK syndrome is clinically characterized by diffuse skin scaling, and palmoplantar keratoderma with constrictive bands around the fingers. It has recently been suggested to be an autoinflammatory keratinization disease 9 . Patient's epidermis shows hyperkeratosis, parakeratosis and hypergranulosis associated with enlarged and abnormally shaped keratohyalin granules together with abnormal distribution of filaggrin in the Stratum granulosum (absence) and Stratum corneum (broader detection) 10 .…”

Congenital Ichthyosis: Clinical and Genetic Characteristics of the Disease

“…Врожденный ихтиоз характеризуется большим разнообразием клинико-генетических вариантов болезни. Представленная нами обзорная информация необходима клиническим специалистам для оценки симптомов заболевания, внешних признаков, анамнестических данных с целью принятия решения о направлении больных на [91,92] Примечание. AР -аутосомно-рецессивный; ХД -X-сцепленный доминантный.…”

Curative Treatment of POMP-Related Autoinflammation and Immune Dysregulation (PRAID) by Hematopoietic Stem Cell Transplantation

“…Upregulation of POMP by interferons (IFN) enhances major histocompatibility complex (MHC)-I dependent antigen presentation and thus the specific T-cell response [ 2 ]. Frameshift variants in POMP escaping nonsense-mediated decay (NMD) are associated with “Proteasome-Related-Autoinflammatory Diseases” (PRAID), whereas autosomal recessive deletions in the 5´-UTR cause “Keratosis Linearis with Ichthyosis Congenita and sclerosing Keratoderma” (KLICK) syndrome, an intrinsic dermatological disorder [ 3 , 4 ]. PRAID are characterized by early-onset immunodeficiency and autoimmunity in combination with non-infectious skin lesions; a presentation also termed CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature) syndrome [ 3 ].…”

“…PRAID are characterized by early-onset immunodeficiency and autoimmunity in combination with non-infectious skin lesions; a presentation also termed CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature) syndrome [ 3 ]. Four PRAID [ 3 , 5 , 6 ] and 14 KLICK syndrome [ 4 ] patients were previously reported (summarized in Online Resource 1 ).…”