Reno S. Bladergroen

A 2‐bp deletion in the GJA1 gene is associated with oculo‐dento‐digital dysplasia with palmoplantar keratoderma

Oculo‐dento‐digital dysplasia (ODDD, OMIM no. 164210) is a pleiotropic disorder characterized mainly by ocular anomalies, varying degrees of finger and toe syndactyly, and enamel defects. It is caused by missense mutations in the gene coding for the gap junction protein connexin 43 or GJA1. Other types of mutations have so far not been reported. Here we describe a Dutch kindred with ODDD showing a new symptom, palmoplantar keratoderma, and associated with a novel 2‐bp deletion mutation of GJA1. The dinucleotide deletion 780_781delTG is located in the cytoplasmic C‐terminal loop and leads to a frameshift. This is predicted to lead to the production of a slightly truncated protein with 46 incorrect amino acids in the C‐terminal cytoplasmic loop (C260fsX307). This novel mutation may explain the presence of skin symptoms.

A missense mutation in the type II hair keratin hHb3 is associated with monilethrix

Monilethrix (MIM #158 000) is an autosomal dominant hair disorder that can cause scarring alopecia in affected individuals.1 Nail changes and keratosis pilaris of the skin of neck and arms have also been described. The hallmark hair abnormality in monilethrix is a beading of the hair shaft caused by periodic narrowing with the nodes separated by about 0.7 mm. The cause of the beading is unknown. The expression of monilethrix is variable.2 In mild cases, dystrophic hairs may be found only on the occiput, but severely affected individuals may suffer complete alopecia. Most cases described so far are associated with mutations in the type II (basic) trichocyte keratin genes hHb1 and hHb6 .2,3,4,5,6,7,8,9,10,11,12,13,14 Both genes have a mutational hotspot in the region coding for the helix termination motif. Most mutations seem to affect the same residues—glutamic acids at positions 413 and 402.3,6,10,15 Mutations affecting the helix initiation motif have also been found.7 From the phenotype, it is apparent that hHb1 and hHb6 are major hair cortex keratins. A third type II trichocyte keratin, hHb3, is expressed in much the same pattern as hHb1.16 From this, it may be expected that mutations of hHb3 may cause monilethrix as well. However, mutations in this gene have so far not been described. We analysed three patients suffering from monilethrix for the presence of mutations in hHb1 , hHb3 , and hHb6 . In one patient, we found a heterozygous missense mutation in hHb3 causing the substitution of a glutamic acid by a lysine at position 407 in the helix termination motif (E407K). This mutation corresponds to the E402K substitution in hHb1 and hHb6, clearly defining this particular residue as a trichocyte keratin …

Combined occurrence of filaggrin mutations and IL‐10 or IL‐13 polymorphisms predisposes to atopic dermatitis

Background:  Although filaggrin mutations are presently believed to play a key role in the development of atopic dermatitis (AD), obviously also immunological factors involved in acquired immune response are important for the development of allergic inflammation.

Novel missense mutations in the FOXC2 gene alter transcriptional activity.

Mutations in the FOXC2 gene that codes for a forkhead transcription factor are associated with primary lymphedema that usually develops around puberty. Associated abnormalities include distichiasis and, very frequently, superficial and deep venous insufficiency. Most mutations reported so far either truncate the protein or are missense mutations in the forkhead domain causing a loss of function. The haplo‐insufficient state is associated with lymphatic hyperplasia in mice as well as in humans. We analyzed the FOXC2 gene in 288 patients with primary lymphedema and found 11 pathogenic mutations, of which 9 are novel. Of those, 5 were novel missense mutations of which 4 were located outside of the forkhead domain. To examine their pathogenic potential we performed a transactivation assay using a luciferase reporter construct driven by FOXC1 response elements. We found that the mutations outside the forkhead domain cause a gain of function as measured by luciferase activity. Patient characteristics conform to previous reports with the exception of distichiasis, which was found in only 2 patients out of 11. FOXC2 mutations causing lymphedema‐distichiasis syndrome reported thus far result in haplo‐insufficiency and lead to lymphatic hyperplasia. Our results suggest that gain‐of‐function mutations may also cause lymphedema. One would expect that in this case, lymphatic hypoplasia would be the underlying abnormality. Patients with activating mutations might present with Meige disease.

A novel mutation in the L12 domain of keratin 1 is associated with mild epidermolytic ichthyosis

Summary Background  Epidermolytic ichthyosis (EI), previously termed bullous congenital ichthyosiform erythroderma or epidermolytic hyperkeratosis, is a clinically heterogeneous genodermatosis caused by mutations in the genes encoding the suprabasal keratins 1 and 10. Classical EI is clinically characterized by severe neonatal erythroderma, blistering and fragile skin in infancy, quickly subsiding with subsequent development of generalized scaling hyperkeratosis. We report three Dutch families with palmoplantar keratoderma and mild blistering, but without neonatal erythroderma and generalized scaling. A novel heterozygous missense mutation in the linker L12 domain of KRT1:c.1019A>G, p.Asp340Gly was found associated with this phenotype in these families.

Biallelic inactivation of protoporphyrinogen oxidase and hydroxymethylbilane synthase is associated with liver cancer in acute porphyrias.

Variegate porphyria (VP) and acute intermittent porphyria (AIP), the two most common types of acute porphyrias (AHPs), result from a partial deficiency of protoporphyrinogen oxidase (PPOX) and hydroxymethylbilane synthase (HMBS), respectively. A rare but serious complication in the AHPs is hepatocellular carcinoma (HCC). However, the underlying pathomechanisms are yet unknown. We performed DNA sequence analysis in cancerous and non-cancerous liver tissue of a VP and an AIP patient, both with HCC. In samples of both cancerous and non-cancerous liver tissues from the patients, we identified the underlying PPOX and HMBS germline mutations, c.1082dupC and p.G111R, respectively. Additionally, we detected a second somatic mutation, only in the cancer tissue i.e., p.L416X in the PPOX gene of the VP patient and p.L220X in the HMBS gene of the AIP patient, both located in trans to the respective germline mutations. Both somatic mutations were not detected in 10 non-porphyria-associated HCCs. Our data demonstrate that in the hepatic cancer tissue of AHP patients, somatic second-hit mutations result in nearly complete inactivation of the enzymes catalyzing major steps in the heme biosynthetic pathway. Both PPOX and HMBS, which might act as tumor suppressors, play a crucial role in the development of HCC in these individuals.

Extended haplotype studies in South African and Dutch variegate porphyria families carrying the recurrent p.R59W mutation confirm a common ancestry.

Background  Variegate porphyria (VP) is due to a partial deficiency of protoporphyrinogen oxidase (PPOX), the seventh enzyme in the haem biosynthetic pathway. Clinically, VP is characterized by photosensitivity and acute neurovisceral attacks that can manifest separately or together in affected individuals. The disease is inherited in an autosomal dominant fashion with incomplete penetrance and PPOX gene mutations associated with VP are usually unique to patients and their families. In South Africa, however, VP is highly prevalent as the result of a founder mutation, designated p.R59W. Previous genealogical and haplotype studies showed a link between South African and Dutch carriers of p.R59W and it was suggested that this mutation was introduced to South Africa by Dutch settlers at the end of the 17th century.

Digenic Inheritance of Mutations in the Coproporphyrinogen Oxidase and Protoporphyrinogen Oxidase Genes in a Unique Type of Porphyria

The simultaneous dysfunction of two enzymes within the heme biosynthetic pathway in a single patient is rare. Not more than 15 cases have been reported. A woman with a transient episode of severe photosensitivity showed a biochemical porphyrin profile suggestive of hereditary coproporphyria (HCP), whereas some of her relatives had a profile that was suggestive of variegate porphyria (VP). HCP and VP result from a partial enzymatic deficiency of coproporphyrinogen oxidase (CPOX) and protoporphyrinogen oxidase (PPOX), respectively. DNA analysis in the index patient revealed mutations in both the CPOX and PPOX genes, designated as c.557-15C>G and c.1289dupT, respectively. The CPOX mutation leads to a cryptic splice site resulting in retention of 14 nucleotides from intron 1 in the mRNA transcript. Both mutations encode null alleles and were associated with nonsense-mediated mRNA decay. Given the digenic inheritance of these null mutations, coupled with the fact that both HCP and VP can manifest with life-threatening acute neurovisceral attacks, the unusual aspect of this case is a relatively mild clinical phenotype restricted to dermal photosensitivity.

Phenotypic variation in epidermolytic ichthyosis : clinical and functional evaluation of the novel p.(Met339Lys) mutation in the L12 domain of KRT1

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