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Biomedical subjects

H P Stevens

Publications and source records attributed to H P Stevens.

At least 19 recordsLinked to original sources
PubMed2002

Diagnosis and confirmation of epidermolytic palmoplantar keratoderma by the identification of mutations in keratin 9 using denaturing high-performance liquid chromatography.

BACKGROUND: Epidermolytic palmoplantar keratoderma (EPPK) is one of a number of disorders characterized by diffuse thickening of palm and sole skin. Although EPPK is not a life-threatening condition, palmoplantar keratoderma can be associated with cancer and heart disease and therefore differential diagnosis is important so that adequate surveillance can be provided for the more serious conditions. Most cases of EPPK are caused by mutations in the gene encoding the palm- and sole-specific keratin 9 (K9), and this provides an option for molecular diagnosis of this condition. OBJECTIVES: To identify the molecular basis of diffuse palmoplantar keratoderma in four British families. METHODS: Denaturing high-performance liquid chromatography (dHPLC) and DNA sequencing were used to screen exon 1 of the k9 gene for sequence variations. RESULTS: The dHPLC profiles obtained from individuals with EPPK differed from control samples, indicating sequence variations within the fragment analysed. The profiles varied between families, suggesting that underlying mutations were different for each family; this was confirmed by DNA sequencing. In three cases previously reported mutations were found that resulted in the change of methionine156 to valine and arginine162 to either tryptophan or glutamine. A novel mutation was identified in a fourth family that changed valine170 to methionine. dHPLC was used to screen control samples for this sequence variation and confirmed that it was not a common polymorphism. CONCLUSIONS: These results confirm the diagnosis of EPPK in these families and underline the usefulness of dHPLC as a method of screening samples for heterozygous mutations.

Chromatography, High Pressure Liquid↗
PubMed2001

Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma.

The adhesive proteins of the desmosome type of cell junction consist of two types of cadherin found exclusively in that structure, the desmogleins and desmocollins, coded by two closely linked loci on human chromosome 18q12.1. Recently we have identified a mutation in the DSG1 gene coding for desmoglein 1 as the cause of the autosomal dominant skin disease striate palmoplantar keratoderma (SPPK) in which affected individuals have marked hyperkeratotic bands on the palms and soles. In the present study we present the complete exon-intron structure of the DSG1 gene, which occupies approximately 43 kb, and intron primers sufficient to amplify all the exons. Using these we have analysed the mutational changes in this gene in five further cases of SPPK. All were heterozygotic mutations in the extracellular domain leading to a truncated protein, due either to an addition or deletion of a single base, or a base change resulting in a stop codon. Three mutations were in exon 9 and one in exon 11, both of which code for part of the third and fourth extracellular domains, and one was in exon 2 coding for part of the prosequence of this processed protein. This latter mutation thus results in the mutant allele synthesising only 25 amino acid residues of the prosequence of the protein so that this is effectively a null mutation implying that dominance in the case of this mutation was caused by haploinsufficiency. The most severe consequences of SPPK mutations are in regions of the body where pressure and abrasion are greatest and where desmosome function is most necessary. SPPK therefore provides a very sensitive measure of desmosomal function.

Base Sequence↗
PubMed2000

Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma.

Desmosomes are major cell adhesion junctions, particularly prominent in the epidermis and cardiac tissue and are important for the rigidity and strength of the cells. The desmosome consists of several proteins, of which desmoplakin is the most abundant. Here, we describe the first recessive human mutation, 7901delG, in the desmoplakin gene which causes a generalized striate keratoderma particularly affecting the palmoplantar epidermis, woolly hair and a dilated left ventricular cardiomyopathy. A number of the patients with this syndromic disorder suffer heart failure in their teenage years, resulting in early morbidity. All tested affected members of three families from Ecuador were homozygous for this mutation which produces a premature stop codon leading to a truncated desmoplakin protein missing the C domain of the tail region. Histology of the skin revealed large intercellular spaces and clustering of desmosomes at the infrequent sites of keratinocyte adhesion. Immunohistochemistry of skin from the patients showed a perinuclear localization of keratin in suprabasal keratinocytes, suggesting a collapsed intermediate filament network. This study demonstrates the importance of desmoplakin in the attachment of intermediate filaments to the desmosome. In contrast to null DESMOPLAKIN: mice which die in early development, the truncated protein due to the homozygous 7901delG mutation in humans is not embryonic lethal. This suggests that the tail domain of desmoplakin is not required for establishing tissue architecture during development.

Amino Acid Sequence↗
PubMed2000

Connexin mutations associated with palmoplantar keratoderma and profound deafness in a single family.

Recently, mutations in two gap junction genes, GJB2 and GJB3 (encoding Connexin 26 and Connexin 31, respectively), have been shown to underlie either inherited hearing loss and skin disease or both disorders. In this study, we have extended our analysis of a small family in which palmoplantar keratoderma and various forms of deafness is segregating. In addition to the previously described sequence variant M34T in GJB2, two other sequence variants were identified: D66H also in GJB2 and R32W in GJB3. As D66H segregated with the skin disease, it is likely to underlie the palmoplantar keratoderma. The other two gap junction variants identified may contribute to the type of hearing impairment and the variable severity of the skin disease in the family.

Connexin 26↗
PubMed1999

Envoplakin, a possible candidate gene for focal NEPPK/esophageal cancer (TOC): the integration of genetic and physical maps of the TOC region on 17q25.

Focal nonepidermolytic palmoplantar keratoderma (NEPPK), or tylosis, is an autosomal, dominantly inherited disorder of the skin that manifests as focal thickening of the palmar and plantar surfaces. In three families studied, the skin disorder cosegregates with esophageal cancer and oral lesions. New haplotype analysis, presented here, places the tylosis esophageal cancer (TOC) locus between D17S1839 and D17S785. Envoplakin (EVPL) is a protein component of desmosomes and the cornified envelope that is expressed in epidermal and esophageal keratinocytes and has been localized to the TOC region. Mutation analysis of EVPL in the three affected families failed to show tylosis-specific mutations, and haplotype analysis of three intragenic sequence polymorphisms of the EVPL gene placed it proximal to D17S1839. Confirmation of the exclusion of EVPL as the TOC gene by location was obtained by integration of the genetic and physical mapping data using radiation hybrid, YAC, BAC, and PAC clones. This new physical map will allow further identification of candidate genes underlying NEPPK associated with esophageal cancer, which may also be implicated in the development of sporadic squamous cell esophageal carcinoma and Barrett's adenocarcinoma.

Base Sequence↗
PubMed1999

The palmoplantar keratodermas: much more than palms and soles.

The inherited palmoplantar keratodermas (PPKs) are a diverse and often clinically confusing branch of the genetic skin diseases. As the name suggests, the lesions of PPK primarily affect the palms and soles of the feet, although a number of the PPKs are also associated with a genetic predisposition to other conditions, including cancer, hearing loss and heart failure. The mapping and identification of genes that underlie the PPKs reveal new insights into the biological interactions of the structural components of the palmoplantar epidermis and further our understanding of epidermal disease. More significantly, by genetically characterizing the PPKs, genes that have a role in life-threatening disorders might also be identified.

Deafness↗
PubMed1999

The gene for hypotrichosis of Marie Unna maps between D8S258 and D8S298: exclusion of the hr gene by cDNA and genomic sequencing.

Hypotrichosis of Marie Unna (MU) is an autosomal dominant hair-loss disorder with onset in childhood. A genomewide search for the gene was performed in a large Dutch family using 400 fluorescent microsatellite markers. Linkage was detected with marker D8S258, and analysis of this family and a further British kindred with additional markers in the region gave a combined maximum two-point LOD score of 13.42, with D8S560. Informative recombinants placed the MU gene in a 2.4-cM interval between markers D8S258 and D8S298. Recently, recessive mutations in the hr gene were reported in families with congenital atrichia, and this gene was previously mapped close to the MU interval. By radiation-hybrid mapping, we placed the hr gene close to D8S298 but were unable to exclude it from the MU interval. This, with the existence of the semidominant murine hr allele, prompted us to perform mutation analysis for this gene. Full-length sequencing of hr cDNA obtained from an affected individual showed no mutations. Similarly, screening of all exons of the hr gene amplified from the genomic DNA of an affected individual revealed no mutations. Analysis of expressed sequences and positional cloning of the MU locus is underway.

Alopecia↗
PubMed1999

N-terminal deletion in a desmosomal cadherin causes the autosomal dominant skin disease striate palmoplantar keratoderma.

The N-terminal extracellular domain of the cadherins, calcium-dependent cell adhesion molecules, has been shown by X-ray crystallography to be involved in two types of interaction: lateral strand dimers and adhesive dimers. Here we describe the first human mutation in a cadherin present in desmosome cell junctions that removes a portion of this highly conserved first extracellular domain. The mutation, in the DSG1 gene coding for a desmoglein (Dsg1), results in the deletion of the first and much of the second beta-strand of the first cadherin repeat and part of the first Ca2+-binding site, and would be expected to compromise strand dimer formation. It causes a dominantly inherited skin disease, striate palmoplantar keratoderma (SPPK), mapping to chromosome 18q12.1, in which affected individuals have marked hyperkeratotic bands on the palms and soles. In a three generation Dutch family with SPPK, we have found a G-->A transition in the 3" splice acceptor site of intron 2 of the DSG1 gene which segregated with the disease phenotype. This causes aberrant splicing of exon 2 to exon 4, which are in-frame, with the consequent removal of exon 3 encoding part of the prosequence, the mature protein cleavage site and part of the first extracellular domain. This mutation emphasizes the importance of this part of the molecule for cadherin function, and of the Dsg1 protein and hence desmosomes in epidermal function.

Amino Acid Sequence↗
PubMed1999

Fine genetic mapping of diffuse non-epidermolytic palmoplantar keratoderma to chromosome 12q11-q13: exclusion of the mapped type II keratins.

Diffuse non-epidermolytic palmoplantar keratoderma (NEPPK) belongs to the heterogeneous group of skin diseases characterized by thickening of the stratum corneum of the palms and soles (1). This autosomal dominant PPK is characterized by a diffuse pattern of palmar and plantar hyperkeratosis giving the affected areas a thickened yellowish appearance with a marked erythematous edge. Linkage of diffuse NEPPK to chromosome 12q11-q13 has been demonstrated in two independent reports (2, 3). In this study, we describe detailed haplotyping with microsatellite markers mapping to this chromosomal region in three diffuse NEPPK pedigrees from the south of England. Fine mapping of a previously identified recombination event and the identification of a common disease haplotype segregating in the three pedigrees places the diffuse NEPPK locus proximal to the type II keratin gene cluster.

Chromosome Mapping↗
PubMed1999

Symmetry and morbidity assessment of unilateral complete cleft lip nose corrected with or without primary nasal correction.

OBJECTIVE: Unilateral complete cleft lip patients treated with or without a primary nasal correction at the time of cleft lip repair were compared to evaluate the relevance of early surgical correction of the nose by using two assessments: nasal symmetry and morbidity. DESIGN, SETTING, PATIENTS: The no nasal correction group (NNC, n = 19) was operated by surgeon A using the Millard technique. The primary nasal correction group (PNC, n = 9) was operated by surgeon B combining the modified Millard technique with a columellar lift and alar mobilization. Symmetry was assessed on two sets of standardized photographs at 9 years of age using a computer-assisted analysis. Both cleft groups were compared with normal controls (NC, n = 20). The computer method included area and angular measurements. Morbidity was assessed by the number of procedures on the vermilion, the lip, and/ or nose for revisional surgery up to the age of 9 (NNC, n = 26; PNC, n = 12). RESULTS: No significant differences in symmetry were found between the NNC and PNC groups regarding the area and angular measurements. With regard to the area measurements, both cleft groups produced a significant asymmetry when compared to the NC group. Concerning the angular measurements, however, the NNC group differed significantly from the NC group, whereas such a difference could not be noted between the PNC group and NC group. With respect to morbidity, no revisional procedures were performed in the PNC group. The number of revisional procedures in the NNC group was 16 in 10 patients. CONCLUSION: Results are presented that favor, up to the age of 9 years, a primary nasal correction at the time of cleft lip repair.

Child↗
PubMed1998

Specialized keratin expression pattern in human ridged skin as an adaptation to high physical stress.

We have analysed the expression of keratins in the epidermis of normal human palm and sole skin (ridged skin) using immunohistochemistry and in situ hybridization. The epidermis of human ridged skin expresses a more complex pattern of keratins than thin skin, which is probably due to the greater stress that ridged skin has to withstand. In addition to keratin K9, we document specific expression patterns of keratins K6, K16 and K17 which are suggestive of regional adaptations of this epidermis to a high cell turnover rate. In particular, the sequestered location of nests of K17-positive cells at the bottom of the deep primary epidermal ridges supports the notion of functional heterogeneity of basal cells and suggests that the K17-positive sites may include stem cells. Expression of K6 and K16 in some basal and most suprabasal keratinocytes is compatible with a constitutively high proliferative activity of normal ridged epidermis, but may also reflect different physical properties of the suprabasal cells, in contrast with regions expressing K9. The distinct labelling patterns observed in primary and secondary epidermal ridges as well as epidermal layers above dermal papillae suggest the existence of local microenvironmental niches leading to differences in keratinocyte differentiation.

Adaptation, Physiological↗
PubMed1997

Connexin 26 mutations in hereditary non-syndromic sensorineural deafness.

Severe deafness or hearing impairment is the most prevalent inherited sensory disorder, affecting about 1 in 1,000 children. Most deafness results from peripheral auditory defects that occur as a consequence of either conductive (outer or middle ear) or sensorineuronal (cochlea) abnormalities. Although a number of mutant genes have been identified that are responsible for syndromic (multiple phenotypic disease) deafness such as Waardenburg syndrome and Usher 1B syndrome, little is known about the genetic basis of non-syndromic (single phenotypic disease) deafness. Here we study a pedigree containing cases of autosomal dominant deafness and have identified a mutation in the gene encoding the gap-junction protein connexin 26 (Cx26) that segregates with the profound deafness in the family. Cx26 mutations resulting in premature stop codons were also found in three autosomal recessive non-syndromic sensorineuronal deafness pedigrees, genetically linked to chromosome 13q11-12 (DFNB1), where the Cx26 gene is localized. Immunohistochemical staining of human cochlear cells for Cx26 demonstrated high levels of expression. To our knowledge, this is the first non-syndromic sensorineural autosomal deafness susceptibility gene to be identified, which implicates Cx26 as an important component of the human cochlea.

Aged↗
PubMed1997

Clinical and financial aspects of cholecystectomy: laparoscopic versus open technique.

Clinical and financial aspects of laparoscopic (LC) (n = 119) and open (OC) (n = 117) cholecystectomy are compared in a retrospective study. The number and nature of perioperative complications do not differ importantly between these techniques. In favor of LC, significant differences are observed regarding the numbers of days severe pain was suffered (mean 1.7 days versus 5.4 days), the total number of days pain was suffered (mean 7.0 days versus 12.2 days), the number of postoperative days in hospital (mean 3.1 days versus 8. 8 days), the extent of perioperative monitoring performed, and the number of days before patients could return to (every day) work (mean 12.8 days versus 34.8 days). In this study total charges for LC (hospital and professional charges) are significantly lower than the total charges for OC [means, in dutch guilders (DG) were 4425 for LC versus 9215 for OC; $1 US = 1.93 DG]. The difference is the result of fewer days of postoperative hospitalization and reduced perioperative screening for LC. Furthermore, hospital charges for LC in The Netherlands (DG 3655) are less expensive than average hospital charges reported so far (US $1894 compared to $4948). For the hospital itself, however, on an annual base LC might well be more expensive than OC because of a maximum quota-annex-budgetizing system installed by the government to keep national health care costs controllable and low. In conclusion, LC has clear advantages over OC in clinical, social, and financial respects. Unjustly, the hospital does not seem to gain financial benefit from this fact.

Adult↗
PubMed1997

A new mutation in the type II hair cortex keratin hHb1 involved in the inherited hair disorder monilethrix.

Monilethrix is a rare dominant hair disease characterized by beaded or moniliform hair which results from the periodic thinning of the hair shaft and shows a high propensity to excess weathering and fracturing. Several cases of monilethrix have been linked to the type II keratin gene cluster on chromosome 12q13 and causative heterozygous mutations of a highly conserved glutamic acid residue (Glu 410 Lys and Glu 410 Asp) in the helix termination motif of the type II hair keratin hHb6 have recently been identified in monilethrix patients of two unrelated families. In the present study, we have investigated two further unrelated monilethrix families as well as a single case. Affected members of one family and the single patient exhibited the prevalent hHb6 Glu 410 Lys mutation. In the second family, we identified in affected individuals a lysine substitution of the corresponding glutamic acid residue, Glu 403, in the type II hair keratin hHb1, suggesting that this site represents a mutational hotspot in these highly related type II hair keratins. Both hHb1 and hHb6 are largely coexpressed in cortical trichocytes of the hair shaft. This indicates that monilethrix is a disease of the hair cortex.

Amino Acid Sequence↗