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Biomedical subjects

W Ahmad

Publications and source records attributed to W Ahmad.

At least 37 records · Page 2Linked to original sources
PubMed2001

Development of guidelines to facilitate improved support of South Asian carers by primary health care teams.

BACKGROUND: Evidence based guidelines are regarded as an appropriate basis for providing effective health care, but few guidelines incorporate the views of users such as carers. AIM: To develop guidelines to assist primary health care teams (PHCTs) in their work with carers within South Asian communities. METHODS: The guidelines were drawn up by a development group consisting of members of teams in areas with South Asian communities (Leicester and Bradford). The teams were invited to make their recommendations based on a systematic review of literature on minority ethnic carers and the findings of a study of the needs and experiences of local South Asian carers. A grading system was devised to enable the teams and a group of expert peer reviewers to assess the quality of evidence in support of each recommendation. RESULTS: The teams agreed seven recommendations, graded according to available evidence and strength of opinion. External peer review supported the PHCTs' interpretation of evidence and their recommendations. The recommendations included consideration of communication and information for carers, coordination of care within teams, and recognition by team members of the roles of carers and their cultural and religious beliefs. CONCLUSION: There are particular steps that PHCTs can take to improve their support of South Asian carers. It is possible to develop guidelines that take users' views into account and incorporate evidence from qualitative studies.

Asia, Western↗
PubMed2001

Identification of a founder mutation in the protoporphyrinogen oxidase gene in variegate porphyria patients from chile.

Variegate porphyria (VP; OMIM 176200) is characterized by a partial defect in the activity of protoporphyrinogen oxidase (PPO), the seventh enzyme of the porphyrin-heme biosynthetic pathway. The disease is usually inherited as an autosomal dominant trait displaying incomplete penetrance. In an effort to characterize the spectrum of molecular defects in VP, we identified 3 distinct mutations in 6 VP families from Chile by PCR, heteroduplex analysis, automated sequencing, restriction enzyme digestion and haplotyping analysis. The mutations consisted of 2 deletions and 1 missense mutation, designated 1239delTACAC, 1330delT and R168H. The occurrence of the missense mutation R168H had been reported previously in American, German and Dutch VP families, suggesting that this may represent a frequent recurrent mutation. Interestingly, the mutation 1239delTACAC was found in patients from 4 unrelated families living in different parts of Chile, suggesting that it might represent a common mutation in Chile. Haplotype analysis using 15 microsatellite markers which closely flank the PPO gene on chromosome 1q22, spanning approximately 21 cM, revealed the presence of R168H on different haplotypes in 6 VP patients from 3 unrelated families. In contrast, we found the occurrence of 1239delTACAC on the same chromosome 1 haplotype in 11 mutation carriers from 4 unrelated families with VP. These findings are consistent with R168H representing a hotspot mutation and 1239delTACAC existing as a founder mutation in the PPO gene. Our data comprise the first genetic studies of the porphyrias in South America and will streamline the elucidation of the genetic defects in VP patients from Chile by allowing an initial screening for the founder mutation 1239delTACAC.

Chile↗
PubMed2000

A novel missense mutation (C622G) in the zinc-finger domain of the human hairless gene associated with congenital atrichia with papular lesions.

Congenital atrichia with papular lesions is a rare, recessively inherited form of hair loss characterized by a complete absence of all body hair shortly after birth. Mutations in the human ortholog of the mouse hairless (hr) gene have been implicated in the pathogenesis of this disorder. In this study, we screened, by direct sequence analysis, the hairless gene in a family of Polish descent and identified a novel missense mutation (C622G). The mutation alters the third of four invariant cysteins in the zinc-finger domain, which has high homology to the C-X-X-C-(X)17-C-X-X-C structure of the zinc-fingers of the GATA family of transcription factors. The human hairless gene encodes a putative transcription factor with restricted expression in the brain and skin, which is involved in the regulation of apoptosis during catagen remodeling in the hair cycle.

Alopecia↗
PubMed2000

Multiple familial cutaneous glomangioma: a pedigree of 4 generations and critical analysis of histologic and genetic differences of glomus tumors.

BACKGROUND: Glomangiomas are benign tumors arising from neuromyoarterial cells surrounding cutaneous arteriovenous anastomoses that serve as temperature regulators. They exist as solitary or multiple types, occurring sporadically or in a familial pattern, the latter of which is rare. OBJECTIVE: We describe a 4-generation pedigree of familial cutaneous glomangioma, in addition to the 3 other well-documented pedigrees reported in the literature to date, and we clarify ways in which to distinguish the different types of glomus tumors. METHODS: Nodular skin lesions of 4 affected family members were analyzed by histologic, immunohistologic, and electron microscopic methods. To elucidate the gene defect in this family, we searched for a linkage to a candidate locus on chromosome 11q23 previously identified in paragangliomas, one form of glomus tumor, in 16 family members of 4 generations by using polymorphic markers. RESULTS: The diagnosis of disseminated cutaneous glomangiomas was confirmed histologically in 4 family members of 3 different generations. Glomangiomas were transmitted in an autosomal dominant pattern via the paternal line. Genetic linkage analysis of the affected family members excluded linkage to chromosome 11q23. CONCLUSION: An autosomal dominant pattern of inheritance has been described for glomus tumors of the paraganglioma type originating from the APUD cell system, the underlying genetic defect of which has been mapped to chromosome 11q23. In contrast, we show that the genetic defect in disseminated cutaneous glomus tumors of the glomangioma type deriving from smooth muscle cells or pericytes is not linked to chromosome 11. Thus we suggest that the common term glomus tumor, used for both paragangliomas and glomangiomas in the current literature, is misleading and should be avoided because these tumors have different histologic derivation and genetic origin.

Adult↗
PubMed1999

Genomic organization of the human hairless gene (HR) and identification of a mutation underlying congenital atrichia in an Arab Palestinian family.

Congenital atrichia is a rare form of hereditary human hair loss, characterized by the complete shedding of hair shortly after birth, together with the formation of papular lesions on the skin. Recently, we cloned the human homolog of the mouse hairless gene and identified pathogenic mutations in several families with inherited congenital atrichia. Here, we present the genomic organization of the human hairless gene (HGMW-approved symbol HR), which spans over 14 kb on chromosome 8p12 and is organized into 19 exons. In addition, we report the identification of a 22-bp deletion mutation in exon 3 of the hairless gene in a large consanguineous Arab Palestinian family from a village near Jerusalem, Israel. These findings extend the body of evidence implicating mutations in the hairless gene as an underlying cause of congenital atrichia in humans.

Alopecia↗
PubMed1999

The molecular basis of congenital atrichia in humans and mice: mutations in the hairless gene.

Congenital atrichia is a form of total alopecia inherited in an autosomal recessive pattern. In individuals affected with this form of hair loss, hairs are typically absent from the scalp, and patients are nearly completely devoid of eyebrows, eyelashes, axillary and pubic hair, following shedding of the natural hair shortly after birth. We have recently linked this disorder to the chromosomal region 8p12, and cloned the human hairless gene, which resides within this interval. We have identified several mutations in the hairless gene in atrichia families from around the world. In hairless mice, the hair matrix cells appear to undergo a premature and massive apoptosis, together with a concomitant decline in Bcl-2 expression, a loss of NCAM positivity, and a disconnection with the overlying epithelial sheath essential for the movement of the dermal papilla. As a consequence, the hair bulb and dermal papilla remain stranded in the dermis, and indispensible messages between the dermal papilla and stem cells in the bulge are not transmitted, so no further hair growth occurs. These findings suggest that the hairless gene product may play a crucial role in maintaining the delicate balance between cell proliferation, differentiation and apoptosis in the hair follicle, as well as in the interfollicular epidermis.

Alopecia↗
PubMed1999

Structure of the human gene for lysosomal di-N-acetylchitobiase.

Chitobiase is a lysosomal glycosidase that acts during the ordered degradation of asparagine-linked glycoproteins to cleave the core chitobiose unit at its reducing end. Human chitobiase is expressed in significant amounts, while bovine chitobiase is produced at extremely low levels. To begin to understand this species-dependent expression, we determined the gene structure of human chitobiase. The human chitobiase gene ( CTB S) is approximately 20 kb comprising seven exons varying from 0.1 to 2.3 kb and six introns of 0.3 to 8 kb. The previously characterized partial bovine chitobiase gene structure is similarly organized including exon and intron sizes and locations, but the human and bovine 5'-flanking regions differ significantly. 5'-RACE analysis of human chitobiase cDNA revealed only one transcriptional start site 45 bp upstream of the ATG translation initiation site. Computer analysis of the human chitobiase gene 5'-flanking region shows characteristics of a typical housekeeping gene. The putative promoter region contains a distal TATA box, and there are several Sp-1 and AP-2 cis elements. In contrast, bovine chitobiase gene 5'-flanking region shows totally different structures and may contain several silencers. A partial art-2 segment which is an artiodactyl Alu -like repetitive sequence, is also present. These evolutionary differences in the 5'-flanking region of the chitobiase genes from human and bovine could account for the widely varied expression levels of the hydrolase within these two species.

Amino Acid Sequence↗
PubMed1999

Identification of a de novo glycine substitution in the type VII collagen gene in a proband with mild dystrophic epidermolysis bullosa.

The dystrophic forms of epidermolysis bullosa result from different types and combinations of mutations in the type VII collagen gene (COL7A1). We describe a novel glycine substitution arising as a de novo mutation in a proband with a clinically mild form of dystrophic epidermolysis bullosa and no family history of any blistering disease. This report underscores the predominance of glycine substitutions in the dominantly inherited forms of dystrophic form epidermolysis bullosa, and heightens our awareness of unusual modes of inheritance. This information is critical for accurate genetic counseling and determination of recurrence risk in families with dystrophic EB.

Base Sequence↗
PubMed1999

Erythropoietic protoporphyria: identification of novel mutations in the ferrochelatase gene and comparison of biochemical markers versus molecular analysis as diagnostic strategies.

BACKGROUND: Erythropoietic protoporphyria (EPP) results from an inherited deficiency of the last enzyme of the heme biosynthetic pathway, ferrochelatase (FC). EPP is usually inherited in an autosomal dominant fashion, and the mutations in the FC gene on chromosome 18q21.3 detected in EPP patients are heterogeneous. METHODS: In this study, we screened the FC gene for mutations in 12 patients from 10 unrelated families with EPP and their family members using heteroduplex analysis, automated sequencing, and restriction enzyme digestion. RESULTS: We detected 8 different mutations in these patients, including 1 missense mutation, 5 frameshift mutations, and 2 splice site mutations, 6 of which are previously undescribed. CONCLUSIONS: We have established the molecular basis of EPP in 10 unrelated families, thereby providing further evidence for the heterogeneity in this disorder. Importantly, molecular diagnosis allowed revisions in the status of several clinically unaffected silent mutation carriers within the families. We compare the value of genetic research strategies with the combination of biochemical data and clinical phenotype as diagnostic tools to confirm a putative diagnosis in EPP.

Biomarkers↗
PubMed1999

Molecular basis of congenital atrichia in humans and mice.

In recent years, molecular genetic approaches to the study of human diseases have yielded unexpected insights into the pathophysiology of many dermatologic disorders, most recently, disorders involving hair loss (i.e., alopecia). In the future, it is anticipated that treatments for many of these disorders will be in the form of gene-based therapies. These approaches would not be possible without a fundamental understanding of the genes that underlie the respective genodermatoses, and how mutations in those genes give rise to the phenotype. In this review, we illustrate how these approaches apply to a rare inherited disorder involving hair loss in humans, known as papular atrichia, and discuss the corresponding mouse models, known as hairless and rhino. It is anticipated that these insights will someday lead to effective, rationally designed, genetic therapies for this group of psychologically devastating disorders, and eventually extend into more complex phenotypes seen in disorders such as alopecia areata and androgenetic alopecia.

Alopecia↗
PubMed1998

Molecular basis for the rhino (hrrh-8J) phenotype: a nonsense mutation in the mouse hairless gene.

The hairless (hr) and rhino (hrrh) mutations are autosomal recessive allelic mutations that map to mouse Chromosome 14. Both hairless and rhino mice have a number of skin and nail abnormalities and develop a striking form of total alopecia at approximately 3-4 weeks of age. The molecular basis of the hairless mouse phenotype was previously found to be the result of a murine leukemia proviral insertion in intron 6 of the hr gene that resulted in aberrant splicing. In this study, we report a 2-bp substitution in exon 4 of the hr gene in a second allele of hr, rhino 8J (hrrh-8J), leading to a nonsense mutation. These findings document the molecular basis of the rhino phenotype for the first time and suggest that rhino is a functional knock-out of the hr gene.

Alleles↗
PubMed1998

Distinct, autosomal recessive form of spondyloepimetaphyseal dysplasia segregating in an inbred Pakistani kindred.

We describe a large inbred kindred from a remote area of Pakistan, comprising eight generations, with a distinct form of spondyloepimetaphyseal dysplasia (SEMD). We evaluated 16 affected individuals: 11 males and 5 females. Analysis of the pedigree strongly suggests autosomal recessive inheritance, and consanguineous loops could account for all the affected individuals being homozygous for the abnormal allele. The clinical findings included short stature evident at birth, short bowed lower limbs, mild brachydactyly, kyphoscoliosis, an abnormal gait, enlarged knee joints, precocious osteoarthropathy, and normal intelligence. Radiographs demonstrated delayed epiphyseal ossification at the hips and knees, platyspondyly with irregular end plates and narrowed joint spaces, diffuse, early osteoarthritic changes, primarily in the spine and hands, and mild brachydactyly. Mild metaphyseal abnormalities were seen predominantly at hips and knees. This distinctive phenotype is distinct from other autosomal recessive forms of SEMD because of the mild degree of metaphyseal involvement, the type of brachydactyly, and the absence of loose joints or other clinical findings.

Abnormalities, Multiple↗
PubMed1998

Alopecia universalis associated with a mutation in the human hairless gene.

There are several forms of hereditary human hair loss, known collectively as alopecias, the molecular bases of which are entirely unknown. A kindred with a rare, recessively inherited type of alopecia universalis was used to search for a locus by homozygosity mapping, and linkage was established in a 6-centimorgan interval on chromosome 8p12 (the logarithm of the odds favoring linkage score was 6.19). The human homolog of a murine gene, hairless, was localized in this interval by radiation hybrid mapping, and a missense mutation was found in affected individuals. Human hairless encodes a putative single zinc finger transcription factor protein with restricted expression in the brain and skin.

Alopecia↗
PubMed1998

Congenital atrichia in five Arab Palestinian families resulting from a deletion mutation in the human hairless gene.

Congenital atrichia is a rare autosomal recessive disorder of hair development, characterized by complete loss of hair shortly after birth. Evidence of linkage to chromosome 8p12 has been established, implicating the human homolog of the mouse hairless (hr) gene as a candidate gene. We have previously identified missense mutations in families with congenital atrichia. Here, we report the first deletion mutation (2147del C) in exon 9 of the human hairless gene leading to a frameshift and downstream premature termination codon in five Palestinian families of Arab origin.

Alopecia↗
PubMed1998

Mutations in orthologous genes in human spondyloepimetaphyseal dysplasia and the brachymorphic mouse.

The osteochondrodysplasias are a genetically heterogeneous group of disorders affecting skeletal development, linear growth and the maintenance of cartilage and bone. We have studied a large inbred Pakistani family with a distinct form of recessively inherited spondyloepimetaphyseal dysplasia (SEMD) and mapped a gene associated with this dwarfing condition to chromosome 10q23-24, a region syntenic with the locus for the brachymorphic mutation on mouse chromosome 19. We identified two orthologous genes, ATPSK2 and Atpsk2, encoding novel ATP sulfurylase/APS kinase orthologues in the respective regions of the human and mouse genomes. We characterized a nonsense mutation in ATPSK2 in the SEMD family and a missense mutation in the region of Atpsk2 encoding the APS kinase activity in the brachymorphic mouse. ATP sulfurylase/APS kinase catalyses the metabolic activation of inorganic sulfate to PAPS, the universal donor for post-translational protein sulfation in all cell types. The cartilage-specificity of the human and mouse phenotypes provides further evidence of the critical role of sulfate activation in the maturation of cartilage extracellular matrix molecules and the effect of defects in this process on the architecture of cartilage and skeletogenesis.

Amino Acid Sequence↗