Takahiro Hamada

Loss of Kindlin-1, a Human Homolog of the Caenorhabditis elegans Actin–Extracellular-Matrix Linker Protein UNC-112, Causes Kindler Syndrome

Kindler syndrome is an autosomal recessive disorder characterized by neonatal blistering, sun sensitivity, atrophy, abnormal pigmentation, and fragility of the skin. Linkage and homozygosity analysis in an isolated Panamanian cohort and in additional inbred families mapped the gene to 20p12.3. Loss-of-function mutations were identified in the FLJ20116 gene (renamed KIND1 [encoding kindlin-1]). Kindlin-1 is a human homolog of the Caenorhabditis elegans protein UNC-112, a membrane-associated structural/signaling protein that has been implicated in linking the actin cytoskeleton to the extracellular matrix (ECM). Thus, Kindler syndrome is, to our knowledge, the first skin fragility disorder caused by a defect in actin-ECM linkage, rather than keratin-ECM linkage.

Autoantibodies to extracellular matrix protein 1 in lichen sclerosus

BACKGROUNDnLichen sclerosus is a common acquired inflammatory disorder of skin and mucous membranes. The aetiology is unknown, although HLA-subtype susceptibility and high rates of other autoimmune disorders suggest that autoantibodies to specific mucocutaneous antigens are involved. The clinicopathological similarities between lichen sclerosus and lipoid proteinosis, which results from mutations in extracellular matrix protein 1 (ECM1), suggest this protein as an autoantigen.nnnMETHODSnWe analysed serum autoantibody profiles in 171 individuals (86 with lichen sclerosus, 85 healthy controls) by immunoblotting of extracts from normal human skin and lipoid proteinosis skin (lacking ECM1). We generated a full-length glutathione-S-transferase fusion protein for ECM1 to confirm specific immunoreactivity. We affinity-purified serum from patients with lichen sclerosus and did indirect immunofluorescence microscopy on normal skin with or without preabsorption with recombinant ECM1.nnnFINDINGSnBy immunoblotting, IgG autoantibodies were found in 20 (67% [95% CI 45-84]) of 30 lichen sclerosus serum samples. The highest titre was 1 in 20. The bands were not detected in ECM1-deficient substrate. These samples, and those from 56 other patients with lichen sclerosus, showed immunoreactivity to the recombinant ECM1 protein (64 of 86 positive; 74% [65-84]). Only six (7% [2-13]) of 85 control serum samples were positive. Affinity-purified IgG from serum of patients with lichen sclerosus labelled skin similarly to a polyclonal antibody to ECM1. The positive staining was blocked by preabsorption with excess recombinant ECM1 protein.nnnINTERPRETATIONnThese findings provide evidence for a specific humoral immune response to ECM1 in lichen sclerosus and offer insight into disease diagnosis, monitoring, and approaches to treatment.

Clinical and molecular characterization of lipoid proteinosis in Namaqualand, South Africa.

Backgroundu2002 Lipoid proteinosis (LiP) is a rare autosomal recessive disorder characterized by a hoarse voice, warty skin infiltration and scarring. Mutations within the extracellular matrix protein 1 (ECM1) gene cause LiP. Since the early 1970s it has been recognized that South Africa has one of the largest groups of LiP patients worldwide, suggesting a probable founder effect. As LiP patients present with considerable clinical variability, this group of patients offers a unique opportunity for genotype–phenotype correlation.

Heterozygous Mutation in the SAM Domain of p63 Underlies Rapp-Hodgkin Ectodermal Dysplasia

Several ectodermal dysplasia syndromes, including Ectrodactyly-Ectodermal dysplasia-Clefting (EEC) and Ankyloblepharon-Ectodermal Dysplasia-Clefting (AEC) syndromes, are known to result from mutations in the p63 gene. We investigated whether Rapp-Hodgkin syndrome (RHS) is also caused by mutations in the p63 gene. We identified a heterozygous de novo germline missense mutation, S545P, in the sterile-alpha-motif (SAM) domain of p63, in a Thai patient affected with RHS. This is the first genetic abnormality to be described in RHS. The amino acid substitution is the most downstream missense mutation in p63 reported thus far. Histological assessment of a skin biopsy from the patient’s palm showed hyperkeratosis and keratinocyte cell-cell detachment in the upper layers of the epidermis, along with numerous apoptotic keratinocytes. Collectively, these investigations demonstrate that RHS is also caused by mutations in p63 and that the clinical similarities to AEC syndrome are paralleled by the nature of the inherent mutation.

Molecular basis of lipoid proteinosis in a Libyan family

Summary Lipoid proteinosis is an autosomal recessive condition associated with variable scarring and infiltration of skin and mucosae. The disorder has recently been shown to result from loss‐of‐function mutations in the extracellular matrix protein 1 gene (ECM1) on 1q21. Extracellular matrix protein 1 has important physiological and biological roles in aspects of epidermal differentiation, binding of dermal collagens and proteoglycans, and in regulation of angiogenesis. Thus far pathogenic mutations have been described in 16 different families with lipoid proteinosis throughout the world. In this report, we describe the clinico‐pathological features of a 10‐year‐old boy with lipoid proteinosis from a consanguineous Libyan family. By direct sequencing of the affected individuals genomic DNA, we identified a homozygous nonsense mutation in exon 2 of the ECM1 gene, Q32X. This mutation is the most 5′ of all ECM1 mutations described thus far and is predicted to ablate the ECM1a, ECM1b and ECM1c splice variants of the ECM1 gene and to result in a severe clinical phenotype. Sequencing of DNA from the affected individuals five siblings revealed that four were heterozygous carriers of Q32X, findings that have important implications for genetic counselling given the high frequency of consanguineous marriages in Libya.

Progressive osseous heteroplasia resulting from a new mutation in the GNAS1 gene

Progressive osseous heteroplasia (OMIM 166350) is a rare autosomal dominant condition that presents in childhood as dermal ossification and may progress deeper to involve subcutaneous fat and connective tissue. Recently, paternally inherited inactivating mutations in the GNAS1 gene on chromosome 20q13 have been implicated in the pathogenesis, although sporadic cases have also been reported. We report a 9‐year‐old British Chinese girl with progressive osseous heteroplasia resulting from a de novo missense mutation (W281R) in the GNAS1 gene. She is of small stature (0.4th centile) and started to develop skin lesions at the age of 9u2003months. These have been confirmed histologically as osteoma cutis. She is of normal intelligence and development and has no dysmorphic features. The GNAS1 gene exhibits imprinting and maternally inherited mutations have previously been shown to result in Albrights hereditary osteodystrophy (OMIM 103580) with pseudohypothyroidism type 1a, whereas paternally inherited mutations result in progressive osseous heteroplasia or the Albrights hereditary osteodystrophy phenotype with pseudopseudohypothyroidism (OMIM 300800). With only nine mutations of the GNAS1 gene reported so far in progressive osseous heteroplasia, this new mutation helps to extend further the genotype–phenotype correlation.

Generalized dystonia and striatal calcifications with lipoid proteinosis

Lipoid proteinosis (LP) is an autosomal recessive disease that typically presents with papular, verrucous, poxlike, or acneiform scars and lesions and hoarseness. LP was recently mapped to the 1q21 locus and shown to result from mutations in the extracellular matrix protein 1 gene (ECM1). Epilepsy, mental retardation, and hippocampal calcifications can occur. The authors describe a patient with generalized dystonia caused by striatal calcifications.

EEC (Ectrodactyly, Ectodermal dysplasia, Clefting) syndrome: heterozygous mutation in the p63 gene (R279H) and DNA-based prenatal diagnosis.

Summary Backgroundu2002Germline mis‐sense mutations in the DNA‐binding domain of the p63 gene have recently been established as the molecular basis for the autosomal dominant EEC (Ectrodactyly, Ectodermal dysplasia, Clefting) syndrome.

Molecular Basis of Lipoid Proteinosis in Two Indian Siblings

To the Editor: Lipoid proteinosis (OMIM 247100) is a rare autosomal recessive genodermatosis that results from loss-of-function mutations in the extracellular matrix protein 1 (ECM1) gene on chromosome 1q21.2 (1, 2). Over 20 pathogenic mutations have been reported, most of which are specific to individual families (1–4). The ECM1 protein has a wide tissue distribution, including skin, where it has a role in epidermal differentiation, binding of dermal fibrils and angiogenesis (5), all of which may be altered in lipoid proteinosis. Two Indian siblings born to non-consanguineous parents, aged 9 and 12 years, were diagnosed with lipoid proteinosis based on clinical and skin biopsy features that included a hoarse voice from infancy, a short thickened tongue and extensive infiltration and scarring of the skin, as well as deposition of periodic acid Schiff (PAS) -positive material around blood vessels and appendages; these clinico-pathological findings were reported recently in this journal (6). We now follow-up this initial report with molecular analysis. Following informed consent, DNA was extracted from peripheral blood samples taken from the affected siblings and their parents using a standard cold water lysis method. Polymerase chain reaction (PCR) amplification of the ECM1 gene was performed using eight pairs of primers spanning all 10 exons and situated in flanking introns, as described in detail elsewhere (2). All PCR products were then purified using QIA quick PCR Purification Kits (Qiagen, Crawley UK) and sequenced directly in an ABI 310 genetic analyser (Applied Biosystems, Warrington, UK). In addition, we deThe Journal of Dermatology Vol. 31: 764–766, 2004

The P25L mutation in the KRT5 gene in a Japanese family with epidermolysis bullosa simplex with mottled pigmentation.

invasion and tumour depth of more than 7 mm are associated with a more aggressive clinical course and poorer prognosis. Given the risk of either recurrence or metastases, patients should undergo a conservative wider excision. This case highlights the diagnostic problems associated with this rare condition and the failure of conventional imaging to detect metastatic disease. We believe that X-ray contrast lymphography, which is able to demonstrate lymphatic collecting trunks and nodes, may have detected metastatic tumour in our patient. However, lymphography is no longer widely available and has now largely been replaced by CT imaging and MRI for cancer staging and by lymphoscintigraphy for the investigation of lymphoedema. Lymphoscintigraphy is a less invasive procedure but is not able to delineate the lymphatics, instead giving a quantitative analysis of lymph drainage. This case also illustrates the increased risk of progression of neoplastic disease in the presence of immunosuppression, which would explain the relatively young age of our patient when he developed EP.