Ken Arita

Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome.

Kindler syndrome (KS) results from pathogenic loss-of-function mutations in the KIND1 gene, which encodes kindlin-1, a focal adhesion and actin cytoskeleton-related protein. How and why abnormalities in kindlin-1 disrupt keratinocyte cell biology in KS, however, is not yet known. In this study, we identified two previously unreported binding proteins of kindlin-1: kindlin-2 and migfilin. Co-immunoprecipitation and confocal microscopy studies show that these three proteins bind to each other and colocalize at focal adhesion in HaCaT cells and normal human keratinocytes. Moreover, loss-of-function mutations in KIND1 result in marked variability in kindlin-1 immunolabeling in KS skin, which is mirrored by similar changes in kindlin-2 and migfilin immunoreactivity. Kindlin-1, however, may function independently of kindlin-2 and migfilin, as loss of kindlin-1 expression in HaCaT keratinocytes by RNA interference and in KS keratinocytes does not affect KIND2 or FBLIM1 (migfilin) gene expression or kindlin-2 and migfilin protein localization. In addition to identifying protein-binding partners for kindlin-1, this study also highlights that KIND1 gene expression and kindlin-1 protein labeling are not always reduced in KS, findings that are relevant to the accurate laboratory diagnosis of this genodermatosis by skin immunohistochemistry.

Oncostatin M Receptor-β Mutations Underlie Familial Primary Localized Cutaneous Amyloidosis

Familial primary localized cutaneous amyloidosis (FPLCA) is an autosomal-dominant disorder associated with chronic skin itching and deposition of epidermal keratin filament-associated amyloid material in the dermis. FPLCA has been mapped to 5p13.1-q11.2, and by candidate gene analysis, we identified missense mutations in the OSMR gene, encoding oncostatin M-specific receptor beta (OSMRbeta), in three families. OSMRbeta is a component of the oncostatin M (OSM) type II receptor and the interleukin (IL)-31 receptor, and cultured FPLCA keratinocytes showed reduced activation of Jak/STAT, MAPK, and PI3K/Akt pathways after OSM or IL-31 cytokine stimulation. The pathogenic amino acid substitutions are located within the extracellular fibronectin type III-like (FNIII) domains, regions critical for receptor dimerization and function. OSM and IL-31 signaling have been implicated in keratinocyte cell proliferation, differentiation, apoptosis, and inflammation, but our OSMR data in individuals with FPLCA represent the first human germline mutations in this cytokine receptor complex and provide new insight into mechanisms of skin itching.

Unusual molecular findings in Kindler syndrome

Kindler syndrome (KS) is a rare inherited skin disorder with blistering and poikiloderma as its main clinical features. It is caused by loss‐of‐function mutations in the C20orf42 (KIND1) gene which encodes kindlin‐1, an actin cytoskeleton–focal contact‐associated protein which is predominantly expressed in keratinocytes. We investigated the molecular basis of KS in a 16‐year‐old Indian boy who had additional clinical findings, including scleroatrophic changes of the hands and feet, pseudoainhum and early onset of squamous cell carcinoma on his foot. Immunostaining for kindlin‐1 in the patient’s skin was completely absent and sequencing of C20orf42 (KIND1) genomic DNA showed a homozygous splice‐site mutation at the ‐6 position, IVS9‐6T→A. Amplification and sequencing of cDNA from the skin revealed aberrant splicing with either deletion of exon 10 or deletion of exons 9, 10 and 11, both of which involve loss of the pleckstrin homology domain of kindlin‐1 that is thought to play a role in cytoskeletal attachment and integrin‐mediated cell signalling. Pathogenic splice‐site mutations at the ‐6 position are unusual and have rarely been reported for any genetic disorder. Collectively, these findings extend the spectrum of clinical and molecular abnormalities in this rare genodermatosis.

New insight into mechanisms of pruritus from molecular studies on familial primary localized cutaneous amyloidosis

Macular and lichen amyloidosis are common variants of primary localized cutaneous amyloidosis (PLCA) in which clinical features of pruritus and skin scratching are associated with histological findings of deposits of amyloid staining on keratinous debris in the papillary dermis. Most cases are sporadic, but an autosomal dominant family history may be present in up to 10% of cases, consistent with a genetic predisposition in some individuals. Familial PLCA has been mapped to a locus on 5p13.1–q11.2 and in 2008 pathogenic heterozygous missense mutations were identified in the OSMR gene, which encodes oncostatin M receptor β (OSMRβ), an interleukin (IL)‐6 family cytokine receptor. OSMRβ is expressed in various cell types, including keratinocytes, cutaneous nerves and nociceptive neurones in dorsal root ganglia; its ligands are oncostatin M and IL‐31. All pathogenic mutations are clustered in the fibronectin‐III repeat domains of the extracellular part of OSMRβ, sites that are critical for receptor dimerization (with either gp130 or IL‐31RA), and lead to defective signalling through Janus kinase‐signal transducers and activators of transcription, extracellular signal‐regulated protein kinase 1/2 and phosphoinositide 3 kinase/Akt pathways. Elucidating the molecular pathology of familial PLCA provides new insight into mechanisms of pruritus in human skin, findings that may have relevance to developing novel treatments for skin itching. This review provides a clinicopathological and molecular update on familial PLCA.

A novel mutation in the VDR gene in hereditary vitamin D-resistant rickets.

Hereditary vitamin D-resistant rickets (HVDRR) (OMIM 277440) is an autosomal recessive disorder caused by mutations in the VDR gene on 12q13.1 and which codes for the vitamin D receptor. Signalling via this receptor regulates gene expression in 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]-responsive cells and is crucial in promoting calcium and phosphate transport across the small intestine and into the circulation. Intestinal absorption of calcium is reduced in subjects with HVDRR, resulting in hypocalcaemia with secondary hyperparathyroidism and hypophosphataemia. The lack of calcium and phosphate compromises normal bone mineralization leading to childhood rickets. Additional symptoms in HVDRR include muscle weakness and convulsions due to hypocalcaemia. Alopecia is also a relatively common feature in HVDRR. Most patients with HVDRR have sparse hair, and some exhibit alopecia totalis, or sometimes universalis. Moreover, the alopecia may be the initial clinical finding in affected neonates. The alopecia seen in HVDRR resembles that seen in congenital atrichia with papular lesions (OMIM 209500) in that both disorders also have clinically and histologically similar skin papules. Congenital atrichia with papular lesions is caused by mutations in the hairless (HR) gene and it is known that the HR and VDR gene products interact and both are required for proper hair cycling. Here we describe a familial case of HVDRR with alopecia and skin papules, in which we found a novel missense mutation in the VDR gene. We also summarize all the previously reported HVDRR cases with VDR mutations, specifically with regard to the presence or absence of alopecia.

Gap junction development in the human fetal hair follicle and bulge region

Background  Gap junctions, composed of connexin (Cx) subunits, are channels that allow intercellular communication between adjacent cells and are thought to play a key role in the regulation of cell proliferation and differentiation. The Cx expression pattern and formation of gap junctions in human fetal hair follicles has yet to be clarified, including the prominent follicular bulge region that is believed to be a site rich in stem cells.

Acral Peeling Skin Syndrome: A Clinically and Genetically Heterogeneous Disorder

Abstract:  Acral peeling skin syndrome (APSS) is a rare, autosomal, recessive genodermatosis characterized by painless spontaneous exfoliation of the skin of the hands and feet at a subcorneal or intracorneal level. It usually presents at birth or appears later in childhood or early adulthood. Some cases result from mutations in the TGM5 gene that encodes transglutaminase 5, which has an important role in cross‐linking cornified cell envelope proteins. We report a new APSS pedigree from Jordan that contains at least 10 affected family members, although sequencing of the TGM5 gene failed to disclose any pathogenic mutation(s). On the basis of probable consanguinity, we performed homozygosity mapping and identified areas of homozygosity on chromosomes 1, 6, 10, 13, and 16, although none of the intervals contained genes of clear relevance to cornification. APSS is a clinically and genetically heterogeneous disorder, and this Jordanian pedigree underscores the likelihood of still further heterogeneity.

Acral peeling skin syndrome

Abstract:  Acral peeling skin syndrome (APSS) is a rare, autosomal, recessive genodermatosis characterized by painless spontaneous exfoliation of the skin of the hands and feet at a subcorneal or intracorneal level. It usually presents at birth or appears later in childhood or early adulthood. Some cases result from mutations in the TGM5 gene that encodes transglutaminase 5, which has an important role in cross‐linking cornified cell envelope proteins. We report a new APSS pedigree from Jordan that contains at least 10 affected family members, although sequencing of the TGM5 gene failed to disclose any pathogenic mutation(s). On the basis of probable consanguinity, we performed homozygosity mapping and identified areas of homozygosity on chromosomes 1, 6, 10, 13, and 16, although none of the intervals contained genes of clear relevance to cornification. APSS is a clinically and genetically heterogeneous disorder, and this Jordanian pedigree underscores the likelihood of still further heterogeneity.