Peter C. van den Akker

Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy

Background IgE-mediated peanut allergy is a complex trait with strong heritability, but its genetic basis is currently unknown. Loss-of-function mutations within the filaggrin gene are associated with atopic dermatitis and other atopic diseases; therefore, filaggrin is a candidate gene in the etiology of peanut allergy. Objective To investigate the association between filaggrin loss-of-function mutations and peanut allergy. Methods Case-control study of 71 English, Dutch, and Irish oral food challenge–positive patients with peanut allergy and 1000 non peanut-sensitized English population controls. Replication was tested in 390 white Canadian patients with peanut allergy (defined by food challenge, or clinical history and skin prick test wheal to peanut ≥8 mm and/or peanut-specific IgE ≥15 kUL−1) and 891 white Canadian population controls. The most prevalent filaggrin loss-of-function mutations were assayed in each population: R501X and 2282del4 in the Europeans, and R501X, 2282del4, R2447X, and S3247X in the Canadians. The Fisher exact test and logistic regression were used to test for association; covariate analysis controlled for coexistent atopic dermatitis. Results Filaggrin loss-of-function mutations showed a strong and significant association with peanut allergy in the food challenge–positive patients (P = 3.0 × 10−6; odds ratio, 5.3; 95% CI, 2.8-10.2), and this association was replicated in the Canadian study (P = 5.4 × 10−5; odds ratio, 1.9; 95% CI, 1.4-2.6). The association of filaggrin mutations with peanut allergy remains significant (P = .0008) after controlling for coexistent atopic dermatitis. Conclusion Filaggrin mutations represent a significant risk factor for IgE-mediated peanut allergy, indicating a role for epithelial barrier dysfunction in the pathogenesis of this disease.

WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations

Werner syndrome (WS) is an autosomal recessive segmental progeroid syndrome caused by null mutations at the WRN locus, which codes for a member of the RecQ family of DNA helicases. Since 1988, the International Registry of Werner syndrome had enrolled 130 molecularly confirmed WS cases from among 110 worldwide pedigrees. We now report 18 new mutations, including two genomic rearrangements, a deep intronic mutation resulting in a novel exon, a splice consensus mutation leading to utilization of the nearby splice site, and two rare missense mutations. We also review evidence for founder mutations among various ethnic/geographic groups. Founder WRN mutations had been previously reported in Japan and Northern Sardinia. Our Registry now suggests characteristic mutations originated in Morocco, Turkey, The Netherlands and elsewhere.

The international dystrophic epidermolysis bullosa patient registry: an online database of dystrophic epidermolysis bullosa patients and their COL7A1 mutations.

Dystrophic epidermolysis bullosa (DEB) is a heritable blistering disorder that can be inherited autosomal dominantly (DDEB) or recessively (RDEB) and covers a group of several distinctive phenotypes. A large number of unique COL7A1 mutations have been shown to underlie DEB. Although general genotype–phenotype correlation rules have emerged, many exceptions to these rules exist, compromising disease diagnosing and genetic counseling. We therefore constructed the International DEB Patient Registry (http://www.deb‐central.org), aimed at worldwide collection and sharing of phenotypic and genotypic information on DEB. As of May 2011, this MOLGENIS‐based registry contains detailed information on 508 published and 71 unpublished patients and their 388 unique COL7A1 mutations, and includes all combinations of mutations. The current registry RDEB versus DDEB ratio of 4:1, if compared to prevalence figures, suggests underreporting of DDEB in the literature. Thirty‐eight percent of mutations stored introduce a premature termination codon (PTC) and 43% an amino acid change. Submission wizards allow users to quickly and easily share novel information. This registry will be of great help in disease diagnosing and genetic counseling and will lead to novel insights, especially in the rare phenotypes of which there is often lack of understanding. Altogether, this registry will greatly benefit the DEB patients. Hum Mutat 32:1100–1107, 2011. ©2011 Wiley‐Liss, Inc.

Split hand/foot malformation due to chromosome 7q aberrations(SHFM1): additional support for functional haploinsufficiency as the causative mechanism.

We report on three patients with split hand/foot malformation type 1 (SHFM1). We detected a deletion in two patients and an inversion in the third, all involving chromosome 7q21q22. We performed conventional chromosomal analysis, array comparative genomic hybridization and fluorescence in situ hybridization. Both deletions included the known genes associated with SHFM1 (DLX5, DLX6 and DSS1), whereas in the third patient one of the inversion break points was located just centromeric to these genes. These observations confirm that haploinsufficiency due to either a simultaneous deletion of these genes or combined downregulation of gene expression due to a disruption in the region between these genes and a control element could be the cause of the syndrome. We review previously reported studies that support this hypothetical mechanism.

Left ventricular outflow tract obstruction: should cardiac screening be offered to first-degree relatives?

Objectives To determine whether offering cardiac screening to relatives of patients with left ventricular outflow tract obstructions (LVOTOs) would be justified. Background LVOTOs have been recognised as a group of congenital heart diseases with ‘high heritability’. One of the LVOTOs, the bicuspid aortic valve, is often asymptomatic, but has become known to be associated with sudden, unexpected cardiac death. However, the need for cardiac screening of first-degree relatives of patients with LVOTO has not been determined owing to the lack of studies in well-defined cohorts of consecutive patients. Methods The families of a cohort of 249 consecutive paediatric patients with LVOTO were offered genetic counselling. Of 182 consenting index patients, 40 patients (22%) appeared to have associated non-cardiac congenital anomalies (LVOTO-NCA). In the other 142 patients with LVOTO, cardiac screening of 449 first-degree relatives was performed. Results Cardiac screening disclosed a cardiac anomaly in 34 first-degree relatives (8%). In 23 (68%) of these the cardiac anomaly was a bicuspid aortic valve. Twenty-four of these anomalies were newly detected by our screening programme (71%). These 34 cardiac anomalies were found in the families of 28 index cases (20%). Conclusions This study shows that of the patients with LVOTO without NCA, 20% had (an) affected first-degree relative(s), frequently with undetected bicuspid aortic valves. These data suggest that cardiac screening of relatives of patients with LVOTO without NCA is justified. This may help prevent sudden, unexpected, cardiac death or life-threatening complications in relatives with undetected bicuspid aortic valves.

An Overview and Online Registry of Microvillus Inclusion Disease Patients and their MYO5B Mutations

Microvillus inclusion disease (MVID) is one of the most severe congenital intestinal disorders and is characterized by neonatal secretory diarrhea and the inability to absorb nutrients from the intestinal lumen. MVID is associated with patient‐, family‐, and ancestry‐unique mutations in the MYO5B gene, encoding the actin‐based motor protein myosin Vb. Here, we review the MYO5B gene and all currently known MYO5B mutations and for the first time methodologically categorize these with regard to functional protein domains and recurrence in MYO7A associated with Usher syndrome and other myosins. We also review animal models for MVID and the latest data on functional studies related to the myosin Vb protein. To congregate existing and future information on MVID geno‐/phenotypes and facilitate its quick and easy sharing among clinicians and researchers, we have constructed an online MOLGENIS‐based international patient registry (www.MVID‐central.org). This easily accessible database currently contains detailed information of 137 MVID patients together with reported clinical/phenotypic details and 41 unique MYO5B mutations, of which several unpublished. The future expansion and prospective nature of this registry is expected to improve disease diagnosis, prognosis, and genetic counseling.

Mechanisms of natural gene therapy in dystrophic epidermolysis bullosa.

Revertant mosaicism has been reported in several inherited diseases, including the genetic skin fragility disorder epidermolysis bullosa (EB). Here, we describe the largest cohort of seven patients with revertant mosaicism and dystrophic EB (DEB), associated with mutations in the COL7A1 gene, and determine the underlying molecular mechanisms. We show that revertant mosaicism occurs both in autosomal dominantly and recessively inherited DEB. We found that null mutations resulting in complete loss of collagen VII and severe disease, as well as missense or splice-site mutations associated with some preserved collagen VII function and a milder phenotype, were corrected by revertant mosaicism. The mutation, subtype, and severity of the disease are thus not decisive for the presence of revertant mosaicism. Although collagen VII is synthesized and secreted by both keratinocytes and fibroblasts, evidence for reversion was only found in keratinocytes. The reversion mechanisms included back mutations/mitotic recombinations in 70% of the cases and second-site mutations affecting splicing in 30%. We conclude that revertant mosaicism is more common than previously assumed in patients with DEB, and our findings will have implications for future therapeutic strategies using the patients naturally corrected cells as a source for cell-based therapies.

The molecular skin pathology of familial primary localized cutaneous amyloidosis

Please cite this paper as: The molecular skin pathology of familial primary localized cutaneous amyloidosis. Experimental Dermatology 2010; 19: 416–423.

New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update

Restrictive dermopathy (RD) is a rare and extremely severe congenital genodermatosis, characterized by a tight rigid skin with erosions at flexure sites, multiple joint contractures, low bone density and pulmonary insufficiency generally leading to death in the perinatal period. RD is caused in most patients by compound heterozygous or homozygous ZMPSTE24 null mutations. This gene encodes a metalloprotease specifically involved in lamin A post-translational processing. Here, we report a total of 16 families for whom diagnosis and molecular defects were clearly established. Among them, we report seven new ZMPSTE24 mutations, identified in classical RD or Mandibulo-acral dysplasia (MAD) affected patients. We also report nine families with one or two affected children carrying the common, homozygous thymine insertion in exon 9 and demonstrate the lack of a founder effect. In addition, we describe several new ZMPSTE24 variants identified in unaffected controls or in patients affected with non-classical progeroid syndromes. In addition, this mutation update includes a comprehensive search of the literature on previously described ZMPSTE24 mutations and associated phenotypes. Our comprehensive analysis of the molecular pathology supported the general rule: complete loss-of-function of ZMPSTE24 leads to RD, whereas other less severe phenotypes are associated with at least one haploinsufficient allele.

RNA-based therapies for genodermatoses

Genetic disorders affecting the skin, genodermatoses, constitute a large and heterogeneous group of diseases, for which treatment is generally limited to management of symptoms. RNA‐based therapies are emerging as a powerful tool to treat genodermatoses. In this review, we discuss in detail RNA splicing modulation by antisense oligonucleotides and RNA trans‐splicing, transcript replacement and genome editing by in vitro‐transcribed mRNAs, and gene knockdown by small interfering RNA and antisense oligonucleotides. We present the current state of these therapeutic approaches and critically discuss their opportunities, limitations and the challenges that remain to be solved. The aim of this review was to set the stage for the development of new and better therapies to improve the lives of patients and families affected by a genodermatosis.