M. van Geel

FRG2, an FSHD candidate gene, is transcriptionally upregulated in differentiating primary myoblast cultures of FSHD patients

Background: Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is associated with partial deletion of the subtelomeric D4Z4 repeat array on chromosome 4qter. This chromosomal rearrangement may result in regional chromatin relaxation and transcriptional deregulation of genes nearby. Methods and results: Here we describe the isolation and characterisation of FRG2, a member of a chromosomally dispersed gene family, mapping only 37 kb proximal to the D4Z4 repeat array. Homology and motif searches yielded no clues to the function of the predicted protein. FRG2 expression is undetectable in all tissues tested except for differentiating myoblasts of FSHD patients, which display low, yet distinct levels of FRG2 expression, partly from chromosome 4 but predominantly originating from its homologue on chromosome 10. However, in non-FSHD myopathy patients only distantly related FRG2 homologues are transcribed, while differentiating myoblasts from healthy controls fail to express any member of this gene family. Moreover, fibroblasts of FSHD patients and control individuals undergoing forced Ad5-MyoD mediated myogenesis show expression of FRG2 mainly originating from chromosome 10. Luciferase reporter assays show that the FRG2 promoter region can direct high levels of expression but is inhibited by increasing numbers of D4Z4 repeat units. Transient transfection experiments with FRG2 fusion-protein constructs reveal nuclear localisation and apparently FRG2 overexpression causes a wide range of morphological changes. Conclusion: The localisation of FRG2 genes close to the D4Z4 repeats on chromosome 4 and 10, their transcriptional upregulation specifically in FSHD myoblast cultures, potential involvement in myogenesis, and promoter properties qualify FRG2 as an attractive candidate for FSHD pathogenesis.

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 …

Skin changes in oculo-dento-digital dysplasia are correlated with C-terminal truncations of connexin 43†

Oculo‐dento‐digital dysplasia (ODDD, OMIM no.164210) is a pleiotropic disorder caused by mutations in the GJA1 gene that codes for the gap junction protein connexin 43. While the gene is highly expressed in skin, ODDD is usually not associated with skin symptoms. We recently described a family with ODDD and palmoplantar keratoderma. Interestingly, mutation carriers had a novel dinucleotide deletion in the GJA1 gene that resulted in truncation of part of the C‐terminus. We speculated, that truncation of the C‐terminus may be uniquely associated with skin disease in ODDD. Here, we describe a patient with ODDD and palmar hyperkeratosis caused by a novel dinucleotide deletion that truncates most of the connexin 43 C‐terminus. Thus, our findings support the notion that such mutations are associated with the occurrence of skin symptoms in ODDD and provide the first evidence for the existence of a genotype–phenotype correlation.

Novel EBP gene mutations in Conradi-Hünermann-Happle syndrome

Summary Background  Conradi–Hünermann–Happle syndrome [X‐linked dominant chondrodysplasia punctata type 2 (CDPX2); MIM no. 302960] is an X‐linked dominant disorder of cholesterol metabolism that causes a wide spectrum of skeletal abnormalities and linear ichthyosiform skin lesions. Mosaicism is probably responsible for the variability of the phenotype.

A newly identified splice site mutation in ZMPSTE24 causes restrictive dermopathy in the Middle East

Restrictive dermopathy (RD) is a severe neonatal inherited skin syndrome of which children die shortly after birth. Clinical features include intrauterine growth retardation, taut translucent and easily eroded skin, multiple joint ankylosis and distinct facial features. RD is usually caused by homozygous or compound heterozygous mutations in ZMPSTE24, predicted to cause loss of function of the encoded zinc metalloproteinase STE24. ZMPSTE24 is essential for the processing of the nuclear intermediate filament protein prelamin A. We report two distantly related children from the United Arab Emirates with RD. Remarkably, they lived up to 2 months, suggesting some residual function of the mutant protein. We sought to confirm the diagnosis by thorough microscopic analysis of patient skin, to identify the causative mutation and to study its functional consequences. A skin biopsy was obtained and processed for light and electron microscopy. Peripheral blood leucocytes were used for DNA and RNA isolation, and detection of prelamin A by immunofluorescence. Analysis of the skin confirmed the earlier reported densely packed collagen bundles and lack of elastin fibres. In both patients a homozygous splice site mutation c.627+1G>C in ZMPSTE24 was identified. Analysis of the ZMPSTE24 mRNA revealed an in‐frame exon 5 skipping. Accumulation of prelamin A could be detected at the nuclear envelope of patient blood lymphocytes. We thus report the first splice site mutation in ZMPSTE24, which is likely to be a founder mutation in the United Arab Emirates. The accumulation of prelamin A at the nuclear periphery is consistent with defective ZMPSTE24 function. Interestingly, a regular blood sample can be used to investigate prelamin A accumulation.

A new type of erythrokeratoderma.

We describe a Dutch man suffering from a previously undescribed erythrokeratoderma associated with palmoplantar keratoderma and circular constrictions of the fingers. No mutations were identified in the genes encoding loricrin, connexin 26, 30, 30.3, 31 and 31.1, and ARS/complex B. There are some similarities between the disorder described here and other palmoplantar keratodermas and erythrokeratodermas, but assignment to a particular disease category is not possible. Hence we propose that we have delineated a novel type of keratoderma.

A new type of erythrokeratoderma, or KLICK syndrome?: reply from authors

SIR, In the January 2005 issue of the British Journal of Dermatology we published the case of a patient with a peculiar type of erythrokeratoderma that we thought to be novel. It consisted of slightly scaling, elevated patchy keratoderma in a starfish configuration with a predilection for the flexures and the extensor sides of the large joints. In addition, there was a circular sclerosis of the fingers and a slight erythroderma. The patient, born from nonconsanguineous parents, was otherwise healthy and had a healthy daugher of his own. Shortly after publication, Dr A. Vahlquist (Uppsala University, Sweden) correctly pointed out to us that the symptoms very much resembled those of the previously described KLICK syndrome. This entity has been recognized for some years in the OMIM database and is characterized by slight ichthyosiform scaling, circular constrictions of digits and a keratoderma of the flexures that is described as linear. Four families with KLICK syndrome have previously been identified: one family in Spain and three families in Sweden (A. Vahlquist, personal communication). Dr Pujol and colleagues have also noted the similarities between the KLICK phenotype and that of our patient. Upon careful evaluation of previously described cases of KLICK syndrome it is obvious that both Dr Vahlquist and Dr Pujol are correct. Instead of a novel type of erythrokeratoderma, our patient has KLICK syndrome. This new case shows that the phenotype is consistent across ethnic groups and definitively establishes KLICK syndrome as a separate nosological entity. What can be learned from this failure to diagnose a patient with a previously described syndrome correctly? We originally interpreted the keratoses as ‘starfish-shaped’ and did not make much of the episode of ichthyosis in the patient’s childhood, as we had no way of confirming it. The same lesions in KLICK syndrome were classified as ‘linear’. When searching OMIM for ‘linear keratoderma’, KLICK syndrome is returned as one of only eight results. The diagnosis was thus missed because of differences in naming the shape of a skin lesion. While no immediate remedy to this semantic problem presents itself, it is probably a good idea to try and think of several synonymous search terms when looking for a diagnosis in a patient with an undiagnosed hereditary disorder. Dermatologists are creative in the naming of skin lesions; it may just be that the intriguingly strange disease that one has witnessed has already been described with a choice of words that may not be immediately obvious.