Dana Fuchs-Telem

Familial Pityriasis Rubra Pilaris Is Caused by Mutations in CARD14

Pityriasis rubra pilaris (PRP) is a papulosquamous disorder phenotypically related to psoriasis. The disease has been occasionally shown to be inherited in an autosomal-dominant fashion. To identify the genetic cause of familial PRP, we ascertained four unrelated families affected by autosomal-dominant PRP. We initially mapped PRP to 17q25.3, a region overlapping with psoriasis susceptibility locus 2 (PSORS2 [MIM 602723]). Using a combination of linkage analysis followed by targeted whole-exome sequencing and candidate-gene screening, we identified three different heterozygous mutations in CARD14, which encodes caspase recruitment domain family, member 14. CARD14 was found to be specifically expressed in the skin. CARD14 is a known activator of nuclear factor kappa B signaling, which has been implicated in inflammatory disorders. Accordingly, CARD14 levels were increased, and p65 was found to be activated in the skin of PRP-affected individuals. The present data demonstrate that autosomal-dominant PRP is allelic to familial psoriasis, which was recently shown to also be caused by mutations in CARD14.

RIN2 Deficiency Results in Macrocephaly, Alopecia, Cutis Laxa, and Scoliosis: MACS Syndrome

Inherited disorders of elastic tissue represent a complex and heterogeneous group of diseases, characterized often by sagging skin and occasionally by life-threatening visceral complications. In the present study, we report on an autosomal-recessive disorder that we have termed MACS syndrome (macrocephaly, alopecia, cutis laxa, and scoliosis). The disorder was mapped to chromosome 20p11.21-p11.23, and a homozygous frameshift mutation in RIN2 was found to segregate with the disease phenotype in a large consanguineous kindred. The mutation identified results in decreased expression of RIN2, a ubiquitously expressed protein that interacts with Rab5 and is involved in the regulation of endocytic trafficking. RIN2 deficiency was found to be associated with paucity of dermal microfibrils and deficiency of fibulin-5, which may underlie the abnormal skin phenotype displayed by the patients.

CEDNIK syndrome results from loss-of-function mutations in SNAP29.

Background  CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis and keratoderma) syndrome is a rare genodermatosis which was shown 5 years ago in one family to be associated with a loss‐of‐function mutation in SNAP29, encoding a member of the SNARE family of proteins. Decrease in SNAP29 expression was found to result in abnormal lamellar granule maturation leading to aberrant epidermal differentiation and ichthyosis.

Short Stature, Onychodysplasia, Facial Dysmorphism, and Hypotrichosis Syndrome Is Caused by a POC1A Mutation

Disproportionate short stature refers to a heterogeneous group of hereditary disorders that are classified according to their mode of inheritance, clinical skeletal and nonskeletal manifestations, and radiological characteristics. In the present study, we report on an autosomal-recessive osteocutaneous disorder that we termed SOFT (short stature, onychodysplasia, facial dysmorphism, and hypotrichosis) syndrome. We employed homozygosity mapping to locate the disease-causing mutation to region 3p21.1-3p21.31. Using whole-exome-sequencing analysis complemented with Sanger direct sequencing of poorly covered regions, we identified a homozygous point mutation (c.512T>C [p.Leu171Pro]) in POC1A (centriolar protein homolog A). This mutation was found to cosegregate with the disease phenotype in two families. The p.Leu171Pro substitution affects a highly conserved amino acid residue and is predicted to interfere with protein function. Poc1, a POC1A ortholog, was previously found to have a role in centrosome stability in unicellular organisms. Accordingly, although centrosome structure was preserved, the number of centrosomes and their distribution were abnormal in affected cells. In addition, the Golgi apparatus presented a dispersed morphology, cholera-toxin trafficking from the plasma membrane to the Golgi was aberrant, and large vesicles accumulated in the cytosol. Collectively, our data underscore the importance of POC1A for proper bone, hair, and nail formation and highlight the importance of normal centrosomes in Golgi assembly and trafficking from the plasma membrane to the Golgi apparatus.

A Mutation in LIPN, Encoding Epidermal Lipase N, Causes a Late-Onset Form of Autosomal-Recessive Congenital Ichthyosis

Autosomal-recessive congenital ichthyoses represent a large and heterogeneous group of disorders of epidermal cornification. Recent data suggest that most of these disorders might result from defective lipid transport and metabolism. In the present study, we describe a late-onset form of recessive ichthyosis in a large consanguineous pedigree. By using a combination of homozygosity mapping and positional candidate-gene screening, we identified a 2 bp deletion in LIPN that segregated with the disease phenotype throughout the family. LIPN encodes one of six acid lipases known to be involved in triglyceride metabolism in mammals . LIPN was found to be exclusively expressed in the epidermis and to be strongly induced during keratinocyte differentiation.

Infantile mitochondrial hepatopathy is a cardinal feature of MEGDEL syndrome (3-methylglutaconic aciduria type IV with sensorineural deafness, encephalopathy and Leigh-like syndrome) caused by novel mutations in SERAC1.

3‐Methylglutaconic aciduria (3‐MGCA) type IV is defined as a heterogeneous group of inborn errors featuring in common 3‐MGCA and associated with primary mitochondrial dysfunction leading to a spectrum of multisystem conditions. We studied four patients who presented at birth with a clinical picture simulating a primary mitochondrial hepatic disorder consistent with the MEGDEL syndrome including 3‐MGCA, sensorineural deafness, encephalopathy and a brain magnetic resonance imaging with signs of Leigh disease. All affected children displayed biochemical features consistent with mitochondrial OXPHOS dysfunction including hepatic mitochondrial DNA depletion in one patient. Homozygosity mapping identified a candidate locus on 6q25.2‐6q26. Using whole exome sequencing, we identified two novel homozygous mutations in SERAC1 recently reported to harbor mutations in MEGDEL syndrome. Both mutations were found to lead to decreased or absent expression of SERAC1. The present findings indicate that infantile hepatopathy is a cardinal feature of MEGDEL syndrome. We thus propose to rename the disease MEGDHEL syndrome.

Non‐syndromic autosomal recessive congenital ichthyosis in the Israeli population

Autosomal recessive congenital ichthyosis (ARCI) is the term given to a complex and heterogeneous group of cornification disorders associated with mutations in at least eight distinct genes. Mutation distribution and prevalence rates are instrumental for the design of diagnostic strategies in ARCI but have not yet been systematically explored in the Israeli population. Previous data suggest that the demographic features specific to Middle Eastern populations, such as a high frequency of consanguineous marriages, may have an effect on the molecular epidemiology of genodermatoses.

Cole Disease Results from Mutations in ENPP1

The coexistence of abnormal keratinization and aberrant pigmentation in a number of cornification disorders has long suggested a mechanistic link between these two processes. Here, we deciphered the genetic basis of Cole disease, a rare autosomal-dominant genodermatosis featuring punctate keratoderma, patchy hypopigmentation, and uncommonly, cutaneous calcifications. Using a combination of exome and direct sequencing, we showed complete cosegregation of the disease phenotype with three heterozygous ENPP1 mutations in three unrelated families. All mutations were found to affect cysteine residues in the somatomedin-B-like 2 (SMB2) domain in the encoded protein, which has been implicated in insulin signaling. ENPP1 encodes ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which is responsible for the generation of inorganic pyrophosphate, a natural inhibitor of mineralization. Previously, biallelic mutations in ENPP1 were shown to underlie a number of recessive conditions characterized by ectopic calcification, thus providing evidence of profound phenotypic heterogeneity in ENPP1-associated genetic diseases.

Erythrokeratoderma variabilis caused by a recessive mutation in GJB3

Background.  Erythrokeratoderma variabilis (EKV) is a rare disorder of cornification usually associated with dominant mutations in the genes GJB3 and GJB4, which code for connexin (Cx)31 and Cx30.3, respectively, and contribute to the formation of functional gap junctions in the epidermis.

An exceptional mutational event leading to Chanarin―Dorfman syndrome in a large consanguineous family

Chanarin–Dorfman syndrome (CDS) is a rare autosomal recessive metabolic disorder featuring congenital ichthyosis combined with pleiomorphic visceral manifestations associated with tissue accumulation of cytoplasmic lipid droplets. Mutations in the ABHD5 gene, encoding a crucial cofactor for adipose triglyceride lipase, have been found to underlie all CDS cases reported to date. The purposed of this study was to ascertain the genetic defect underlying CDS in a large multigenerational family. We used a combination of direct sequencing, reverse transcriptase–polymerase chain reaction (RT‐PCR) and microsatellite marker genotyping to identify a novel CDS‐causing mutation in ABHD5. Although no pathogenic mutation could be identified in the coding sequence of the ABHD5 gene, polymorphic marker genotyping analysis supported linkage to this gene locus. Accordingly, direct sequencing of RT‐PCR amplification products generated from patient skin‐derived total RNA, revealed in all four patients the presence of a 101 bp insertion between exon 3 and exon 4. Bioinformatic analysis and direct sequencing indicated that this insertion resulted from an exceptional mutational event, namely, the insertion of a LINE element into intron 3 of the ABHD5 gene, leading to aberrant splicing out of the mutant intron 3. Our results confirm genetic homogeneity in CDS and underscore the importance of RNA studies in the molecular diagnosis of genodermatoses.