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Biomedical subjects

Michel van Geel

Publications and source records attributed to Michel van Geel.

11 recordsLinked to original sources
PubMed2006

Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dubé patients.

Birt-Hogg-Dubé (BHD) syndrome is an autosomal-dominantly inherited cancer syndrome characterized by fibrofolliculomas, lung cysts leading to pneumothorax, and chromophobic/oncocytic renal cell carcinoma. The disease is caused by heterozygous mutations in the BHD gene encoding folliculin and all mutations reported putatively lead to protein truncation. Although the function of folliculin is unknown, it is thought to be a tumor suppressor, with loss of heterozygosity (LOH) initiating tumor formation. Here, we report on four novel BHD gene mutations, including two splice-site mutations, in patients presenting with skin lesions only. We further show that LOH cannot be detected in fibrofolliculomas from three patients, suggesting that for the manifestation of cutaneous tumors in BHD syndrome haplo-insufficiency of folliculin is sufficient to initiate uncontrolled growth. Renal microscopic oncocytosis in BHD is considered as a precursor to malignant kidney tumors and may likewise be the result of haplo-insufficiency, with somatic second-hit mutations or LOH giving rise to malignancy later in life.

Adult↗
PubMed2006

Mutation S233L in the 1B domain of keratin 1 causes epidermolytic palmoplantar keratoderma with "tonotubular" keratin.

Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant genodermatosis characterized by epidermolytic hyperkeratosis restricted to the palm and sole epidermis. The disorder is normally associated with dominant-negative mutations in the keratin 9 (K9) gene; however, a small number of cases have been reported where causative mutations were identified in the K1 gene. Here, we present two unrelated Dutch EPPK families with striking ultrastructural findings: tubular keratin structures in the cytoplasm of suprabasal cells. Similar structures were reported previously in a German EPPK family and were termed "tonotubular" keratin. After excluding the involvement of the K9 gene by complete sequencing, we identified a novel mutation, S233L, at the beginning of the 1B domain of K1 in both families. Protein expression studies in cultured cells indicated pathogenicity of this mutation. This is the first report of a genetic defect in this domain of K1. The unusual gain-of-function mutation points to a subtle role of the 1B domain in mediating filament-filament interactions with regular periodicity.

Humans↗
PubMed2006

Diffuse and segmental variants of cutaneous leiomyomatosis: novel mutations in the fumarate hydratase gene and review of the literature.

Multiple cutaneous and uterine leiomyomatosis (MCUL; OMIM 150800) is an autosomal dominantly inherited disease characterized by leiomyomas of the skin and uterine leiomyomas. Recently, association of MCUL with different forms of renal cancer has been described. This syndrome is referred to as hereditary leiomyomatosis and renal cell cancer (OMIM 605839). Both disorders result from heterozygous germline mutations in the fumarate hydratase (FH) gene that may function as a tumor suppressor. Interestingly, cutaneous leiomyomas do not only manifest in a diffuse and symmetric fashion. Rather frequently, a segmental or band-like manifestation pattern can be observed, usually following the lines of Blaschko. Here, we sought to elucidate the molecular basis of diffuse and segmental cutaneous leiomyomatosis in six unrelated Dutch and Spanish patients and their families. We identified six novel FH mutations, including one missense and one nonsense mutation, two deletions and two splice-site mutations. The segmental phenotype that was observed in various patients with FH mutations most likely reflects a type 2 segmental manifestation of cutaneous leiomyomatosis as previously also described for other autosomal dominantly inherited skin diseases. The results presented here extend the current data on the molecular basis of familial cutaneous leiomyomatosis and comprise, to the best of our knowledge, the first genetic study in Dutch and Spanish patients with this disorder. In addition, we review the clinical and molecular aspects of the disease.

Amino Acid Sequence↗
PubMed2005

A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome.

Peeling skin syndrome is an autosomal recessive genodermatosis characterized by the shedding of the outer epidermis. In the acral form, the dorsa of the hands and feet are predominantly affected. Ultrastructural analysis has revealed tissue separation at the junction between the granular cells and the stratum corneum in the outer epidermis. Genomewide linkage analysis in a consanguineous Dutch kindred mapped the gene to 15q15.2 in the interval between markers D15S1040 and D15S1016. Two homozygous missense mutations, T109M and G113C, were found in TGM5, which encodes transglutaminase 5 (TG5), in all affected persons in two unrelated families. The mutation was present on the same haplotype in both kindreds, indicating a probable ancestral mutation. TG5 is strongly expressed in the epidermal granular cells, where it cross-links a variety of structural proteins in the terminal differentiation of the epidermis to form the cornified cell envelope. An established, in vitro, biochemical cross-linking assay revealed that, although T109M is not pathogenic, G113C completely abolishes TG5 activity. Three-dimensional modeling of TG5 showed that G113C lies close to the catalytic domain, and, furthermore, that this glycine residue is conserved in all known transglutaminases, which is consistent with pathogenicity. Other families with more-widespread peeling skin phenotypes lacked TGM5 mutations. This study identifies the first causative gene in this heterogeneous group of skin disorders and demonstrates that the protein cross-linking function performed by TG5 is vital for maintaining cell-cell adhesion between the outermost layers of the epidermis.

Binding Sites↗
PubMed2004

A phenotype resembling the Clouston syndrome with deafness is associated with a novel missense GJB2 mutation.

Mutations in GJB2 (connexin26) are associated with skin disorders and deafness. The Clouston syndrome (MIM129500) is associated with mutations in GJB6 (connexin30). Here, we describe a patient suffering from a Clouston-syndrome-like phenotype of thin hair, deafness, nail dystrophy, and mild erythrokeratoderma, caused by a novel spontaneous missense mutation in GJB2. The heterozygous mutation in codon 42, AAC>AAG, changes asparagine to lysine (N14K). Interestingly, this asparagine is near two of the residues mutated in Keratitis-like ichthyosis deafness (KID) syndrome (G12R and S17F), yet the phenotype associated with N14K strongly differs from the KID phenotype. Instead, there is a clear phenotypic overlap with syndromes associated with connexin26 or 30 mutations. Our finding suggest that careful audiological evaluation of patients suffering from Clouston-syndrome-like phenotypes is warranted and expand the spectrum of connexin26-associated disease.

Amino Acid Sequence↗
PubMed2003

Clouston syndrome can mimic pachyonychia congenita.

We studied three families suffering from nail abnormalities who had previously been diagnosed as pachyonychia congenita. No keratin gene mutations were detected. Sequencing of connexin 30 (GJB6 gene) in these patients identified heterozygous missense mutations G11R and A88V that are known to be associated with Clouston syndrome. This unexpected finding expands the Clouston syndrome phenotype and suggests that some patients diagnosed with pachyonychia may in fact be suffering from Clouston syndrome.

Adolescent↗
PubMed2002

Genomic analysis of human chromosome 10q and 4q telomeres suggests a common origin.

The subtelomeric region of human chromosome 4q contains the locus for facioscapulohumeral muscular dystrophy (FSHD). The FSHD mutation is a deletion within an array of 3.3-kb tandem repeats (D4Z4). The disease mechanism is unknown but is postulated to involve position effect. A closely related 3.3-kb array on chromosome 10qter, in contrast, is not associated with a disease phenotype. We show here that the 4q homology on chromosome 10 is not confined to the 3.3-kb repeats but extends both proximally (42 kb) and distally to include the telomere. We have also identified the most distal expressed gene on 10q known so far, mapping only 96 kb from the 3.3-kb repeat array. A 4q variant has also been identified; there is 92%nucleotide identity between the two 4q forms, 4qA and 4qB. The 4qter and 10qter forms show homology to other chromosome ends, including 4p, 21q, and 22q, and these regions may represent a relatively common subtelomeric domain.

Amino Acid Sequence↗
PubMed2002

A novel connexin 26 mutation in a patient diagnosed with keratitis-ichthyosis-deafness syndrome.

Keratitis-ichthyosis-deafness syndrome is a rare disorder characterized by erythrokeratoderma, deafness, and keratitis. Scarring alopecia and squamous cell carcinoma can also occur. Most cases described so far were sporadic. Here we present evidence that keratitis-ichthyosis-deafness syndrome is caused by a mutation in the connexin 26 gene. This finding expands the spectrum of disorders caused by defects in connexin 26 and implies the gene in normal corneal function, hair growth, and carcinogenesis.

Adult↗
PubMed2001

A cascade of complex subtelomeric duplications during the evolution of the hominoid and Old World monkey genomes.

Subtelomeric duplications of an obscure tubulin "genic" segment located near the telomere of human chromosome 4q35 have occurred at different evolutionary time points within the last 25 million years of the catarrhine (i.e., hominoid and Old World monkey) evolution. The analyses of these segments reported here indicate an exceptional level of evolutionary instability. Substantial intra- and interspecific differences in copy number and distribution are observed among cercopithecoid (Old World monkey) and hominoid genomes. Characterization of the hominoid duplicated segments reveals a strong positional bias within pericentromeric and subtelomeric regions of the genome. On the basis of phylogenetic analysis from predicted proteins and comparisons of nucleotide-substitution rates, we present evidence of a conserved b-tubulin gene among the duplications. Remarkably, the evolutionary conservation has occurred in a nonorthologous fashion, such that the functional copy has shifted its positional context between hominoids and cercopithecoids. We propose that, in a chimpanzee-human common ancestor, one of the paralogous copies assumed the original function, whereas the ancestral copy acquired mutations and eventually became silenced. Our analysis emphasizes the dynamic nature of duplication-mediated genome evolution and the delicate balance between gene acquisition and silencing.

Animals↗