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Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren 1 . We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin ( FLG ) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of ∼4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.

Birgitte Lane and colleagues show that Ferguson-Smith disease, an autosomal dominant skin cancer condition characterized by the development of multiple self-healing tumors, is caused by a disease-specific spectrum of mutations in TGFBR1 . Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith disease (FSD), is an autosomal-dominant skin cancer condition characterized by multiple squamous-carcinoma–like locally invasive skin tumors that grow rapidly for a few weeks before spontaneously regressing, leaving scars 1 , 2 . High-throughput genomic sequencing of a conservative estimate (24.2 Mb) of the disease locus on chromosome 9 using exon array capture identified independent mutations in TGFBR1 in three unrelated families. Subsequent dideoxy sequencing of TGFBR1 identified 11 distinct monoallelic mutations in 18 affected families, firmly establishing TGFBR1 as the causative gene. The nature of the sequence variants, which include mutations in the extracellular ligand-binding domain and a series of truncating mutations in the kinase domain, indicates a clear genotype-phenotype correlation between loss-of-function TGFBR1 mutations and MSSE. This distinguishes MSSE from the Marfan syndrome–related disorders in which missense mutations in TGFBR1 lead to developmental defects with vascular involvement but no reported predisposition to cancer.

Mutations in the filament aggregating protein (filaggrin) gene have recently been identified as the cause of the common genetic skin disorder ichthyosis vulgaris (IV), the most prevalent inherited disorder of keratinization. The main characteristics of IV are fine-scale on the arms and legs, palmar hyperlinearity, and keratosis pilaris. Here, we have studied six Irish families with IV for mutations in filaggrin. We have identified a new mutation, 3702delG, in addition to further instances of the reported mutations R501X and 2282del4, which are common in people of European origin. A case of a 2282del4 homozygote was also identified. Mutation 3702delG terminates protein translation in filaggrin repeat domain 3, whereas both recurrent mutations occur in repeat 1. These mutations are semidominant: heterozygotes have an intermediate phenotype most readily identified by palmar hyperlinearity and in some cases fine-scale and/or keratosis pilaris, whereas homozygotes or compound heterozygotes generally have more marked ichthyosis. Interestingly, the phenotypes of individuals homozygous for R501X, 2282del4, or compound heterozygous for R501X and 3702delG, were comparable, suggesting that mutations located centrally in the filaggrin repeats are also pathogenic.

Irwin McLean and colleagues report that heterozygous loss-of-function mutations in AAGAB , which encodes a cytosolic protein implicated in vesicular trafficking, cause punctate palmoplantar keratoderma. They further show that knockdown of AAGAB in keratinocytes leads to increased cell proliferation accompanied by highly elevated levels of epidermal growth factor receptor. Palmoplantar keratodermas (PPKs) are a group of disorders that are diagnostically and therapeutically problematic in dermatogenetics 1 , 2 , 3 . Punctate PPKs are characterized by circumscribed hyperkeratotic lesions on the palms and soles with considerable heterogeneity. In 18 families with autosomal dominant punctate PPK, we report heterozygous loss-of-function mutations in AAGAB , encoding α- and γ-adaptin–binding protein p34, located at a previously linked locus at 15q22. α- and γ-adaptin–binding protein p34, a cytosolic protein with a Rab-like GTPase domain, was shown to bind both clathrin adaptor protein complexes, indicating a role in membrane trafficking. Ultrastructurally, lesional epidermis showed abnormalities in intracellular vesicle biology. Immunohistochemistry showed hyperproliferation within the punctate lesions. Knockdown of AAGAB in keratinocytes led to increased cell division, which was linked to greatly elevated epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation. We hypothesize that p34 deficiency may impair endocytic recycling of growth factor receptors such as EGFR, leading to increased signaling and cellular proliferation.

MSSE (Ferguson-Smith disease) is a rare familial condition in which multiple skin tumors resembling squamous carcinomas invade locally and then regress spontaneously after several months, leaving disfiguring scars. We review evidence from haplotype studies in MSSE families with common ancestry that the condition is caused by loss of function mutations in TGFBR1 interacting with permissive variants at a second linked locus on the long arm of chromosome 9. The spectrum of TGFBR1 mutations in MSSE and the allelic disorder Loeys Dietz syndrome (characterized by developmental anomalies and thoracic aortic aneurysms) differ. Reports of patients with both MSSE and Loeys Dietz syndrome are consistent with variants at a second locus determining whether self-healing epitheliomas occur in patients with the loss of function mutations found in most MSSE patients or the missense mutations in the intracellular kinase domain of TGFBR1 that characterize Loeys Dietz syndrome.

DEHAL1, the gene encoding iodotyrosine deiodinase in the thyroid, allows for the reuse of iodide for thyroid hormone synthesis. The authors identified four patients from three unrelated families with three unique mutations; all had a dramatic reduction of in vitro iodotyrosine deiodinase activity. Patients had severe goitrous hypothyroidism, evident in infancy and childhood. Infants with DEHAL1 defects may have normal thyroid function at birth and thus may be missed by neonatal screening programs. DEHAL1, the gene encoding iodotyrosine deiodinase in the thyroid, allows for the reuse of iodide for thyroid hormone synthesis. The authors identified four patients from three unrelated families with three unique mutations; all had a dramatic reduction of in vitro iodotyrosine deiodinase activity. Iodine is an essential component of thyroid hormone. To ensure that iodine is available for thyroid hormone biosynthesis, two highly specialized systems evolved in the thyroid gland. One, the sodium–iodide symporter, accumulates iodide in thyroid cells by active membrane transport. 1 The other recycles iodide through the deiodination of monoiodotyrosine and diiodotyrosine, the main iodinated by-products of the synthesis of thyroid hormone. 2 – 4 This enzyme activity is known to exist in the thyroid, liver, and kidneys. 5 Three decades ago, the partial purification of a flavoprotein from bovine thyroid was reported and found to deiodinate iodotyrosines. 6 However, the molecular nature of this . . .

Germline SDHA mutations are reported in a minority of pheochromocytoma/paraganglioma (PPGL) cases but are associated with an increased risk of malignancy, leading some to advocate cascade genetic testing and surveillance screening of “at-risk” first-degree relatives. However, such approaches rely on accurate estimates of variant pathogenicity and disease penetrance, which may have been subject to ascertainment and reporting biases, although the recent provision of large population-based DNA sequence data sets may provide a potentially unbiased resource to aid variant interpretation. Thus, the aim of the current study was to evaluate the pathogenicity and penetrance of SDHA variants reported in literature-based PPGL cases by comparing their frequency to those occurring in the Genome Aggregation Database (GnomAD) data set, which provides high-quality DNA sequence data on 138,632 individuals. In total, 39 different missense or loss-of-function (LOF) SDHA variants were identified in 95 PPGL index cases. Notably, many of the PPGL-associated SDHA alleles were observed at an unexpectedly high frequency in the GnomAD cohort, with ~1% and ~0.1% of the background population harboring a rare missense or LOF variant, respectively. Although the pathogenicity of several SDHA alleles was supported by significant enrichment in PPGL cases relative to GnomAD controls, calculations of disease penetrance based on allele frequencies in the respective cohorts resulted in much lower estimates than previously reported, ranging from 0.1% to 4.9%. Thus, although this study provides support for the etiological role of SDHA in PPGL formation, it suggests that most variant carriers will not manifest PPGLs and are unlikely to benefit from periodic surveillance screening.Germline SDHA variants are enriched in patients with pheochromocytoma/paraganglioma but are associated with very low disease penetrance such that most variant carriers will not manifest disease.

Mutations inactivating the STS gene cause X-linked ichthyosis (XLI), whereas null mutations in the FLG gene cause ichthyosis vulgaris. Two brothers presented with XLI. One had a typical fine scaling, and the other was much more severely affected. Both patients carried STS missense mutation T165I. Furthermore, the more severely affected patient also carried heterozygous FLG mutation R501X, which was absent from his mildly affected brother. These data suggest that disrupting epidermal differentiation via different pathways can increase phenotypic severity. Owing to the high population frequency of FLG mutations, filaggrin is a possible genetic modifier in other genodermatoses.

Germline mutations in the succinate dehydrogenase subunit genes SDHB, SDHC, and SDHD are the most frequent causes of inherited phaeochromocytomas and paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. Our aim was to provide estimates of penetrance and genotype–phenotype correlations in a large cohort of succinate dehydrogenase mutation carriers. We undertook a retrospective survey of 800 individuals in the UK (401 previously reported) with germline mutations in SDHB (620), SDHC (31), and SDHD (149). We estimated and compared tumour risks for each gene according to age using survival analysis and Cox proportional hazards modelling with the statistical programming language R. DUET, a computational approach for predicting the effects of mutations on protein stability, was used to evaluate the functional effects of SDHB and SDHD mutations. Analysis of age-related tumour risks provided novel estimates of penetrance. In addition to tumour-specific differences in risk for individual genes, we confirmed that the SDHD p.Pro81Leu mutation had a distinct phenotype, with a low risk of phaeochromocytoma and extra-adrenal paraganglioma (only one case in 55 patients), and found evidence suggesting higher penetrance with SDHB p.Ile127Ser mutations. Comparison of age-dependent penetrance of disease in p.Ile127Ser carriers versus other SDHB missense mutation carriers showed that p.Ile127Ser was associated with a higher overall penetrance of phaeochromocytoma and paraganglioma (χ2=4·49, p=0·034). SDHB p.Ile127Ser was predicted by DUET to be the most destabilising SDHB missense mutation, through disruption of key intramolecular hydrophobic interactions by the introduction of a polar serine. The penetrance in SDHB and SDHD mutation-positive non-probands by age 60 years was 22·1% (95% CI 15·6–28·3) and 47·5% (29·3–61·1), respectively, and the risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4·2% (1·1–7·2). Increased knowledge of the lifetime tumour risks is crucial to long-term surveillance and management. Knowledge of the molecular basis of the phenotypic variability commonly observed in individuals with germline SDHB, SDHC, and SDHD mutations will facilitate the development of personalised management based on gene-specific and mutation-specific tumour risks. East Anglian Foundation Programme (KAA), University of Cambridge (KAA), NIHR Cambridge Biomedical Research Centre (KAA and ERM), British Heart Foundation (ERM), NHMRC CJ Martin Fellowship (APP1072476) (DBA), Fundação de Amparo a Pesquisa do Estado de Minas Gerais and Centro de Pesquisas René Rachou (CPqRR/FIOCRUZ Minas) (DEVP).