Variegate porphyria (VP; OMIM 176200) is characterized by a partial defect in the activity of pro... more 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.
The hairless and rhino mutations are autosomal recessive allelic mutations that map to mouse Chro... more The hairless and rhino mutations are autosomal recessive allelic mutations that map to mouse Chromosome 14. In general, the rhino phenotype is a more severe manifestation of the hairless phenotype. In both hairless and rhino mice, the hair begins shedding in a cephalocaudal pattern within 7 days after birth, and never regrows due to a series of irreversible cellular events. The hairless mutation closely resembles the human disease known as papular atrichia (MIM 209500). Recently, this disease was linked to Chromosome 8p12, the human homolog of hairless was cloned and mapped to the same locus, and mutations have been identified in several different families. In order to gain insight into the pathophysiology of disease in papular atrichia, we sought to utilize mouse mutations as in vivo model systems. In this study, we report the identification of a homozygous nonsense mutation in the coding region of the hr gene in a hairless mouse captured on a chicken farm in the Midwestern United States. To reflect the place of identification of this new mutation at the hr locus, we have designated this allele hrrhChr using the laboratory code Chr (Christiano).
The recent discovery of the human counterpart of the hairless mouse phenotype 1 has helped our un... more The recent discovery of the human counterpart of the hairless mouse phenotype 1 has helped our understanding of the molecular genetics of hair growth. But there are no reports of a defect in the human homologue of the best known of the 'bald' mouse phenotypes, the nude ...
The human desmoglein genes, desmogleins 1--3, are members of the desmosomal cadherin superfamily,... more The human desmoglein genes, desmogleins 1--3, are members of the desmosomal cadherin superfamily, and encode critical components of the desmosome. These genes are tightly clustered within 150--200 kb of chromosome 18q12.1 and represent excellent candidate genes for genetic disorders of the epidermis linked to this region of the genome. Mutations in desmoglein 1 have already been implicated in the genetic disorder striate palmoplantar keratoderma. Similarly, a mutation in desmoglein 3 underlies the balding mouse phenotype, although no human mutations in desmoglein 3 have been identified to date. In this study, we have characterized the genomic organization of two of the three desmoglein genes mapped to chromosome 18q12. Comparison of their exon-intron structure reveals the high level of evolutionary conservation expected from these related genes. The identification of the genomic structure of the desmoglein genes will facilitate mutation detection in genodermatoses with desmosomal abnormalities resulting from underlying defects in these genes.
The present authors have previously described a consanguineous Pakistani family with fibular hypo... more The present authors have previously described a consanguineous Pakistani family with fibular hypoplasia and complex brachydactyly (DuPan syndrome) inherited as an autosomal recessive trait. All affected individuals showed either reductions or absence of bones in the limbs, and appendicular bone dysmorphogenesis with unaffected axial bones. Obligate heterozygote parents were phenotypically normal. Mutations in the cartilage-derived morphogenetic protein 1 (CDMP1) gene have been reported in two acromesomelic chondrodysplasias (i.e. Hunter–Thompson type and Grebe type) which are phenotypically related to DuPan syndrome. CDMP1, a member of the transforming growth factor β super-family of secreted signalling molecules, has been reported to regulate limb patterning and distal bone growth. Therefore, the present authors examined genomic DNA from the family with DuPan syndrome for mutations in the CDMP1 gene. Affected individuals were homozygous for a missense mutation, T1322C, in the coding region of the CDMP1 gene. This mutation was not found in 44 control subjects of Pakistani origin. The T1322C change predicts a leu441pro substitution in the mature domain of the CDMP1 protein. This is likely to cause a conformational change in the CDMP1 protein that influences the expression of genes which are required for normal bone development. This finding extends the spectrum of phenotypes produced by defects in the CDMP1 gene.
Autosomal recessive hypotrichosis is a rare form of alopecia characterized by sparse hair on scal... more Autosomal recessive hypotrichosis is a rare form of alopecia characterized by sparse hair on scalp, sparse to absent eyebrows and eyelashes, and sparse auxiliary and body hair. Previously, for this form of hypotrichosis, two loci LAH (localized hereditary hypotrichosis) and AH (autosomal recessive hereditary hypotrichosis) have been mapped on chromosome 18q12.1 and 3q27.2, respectively. In the study presented here, we report the localization of a third locus for autosomal recessive form of hypotrichosis in two large Pakistani families. The patients in the two families exhibited typical features of the hereditary hypotrichosis. Genome scan using polymorphic microsatellite markers mapped the gene on chromosome 13q14.11–q21.32. A maximum combined two-point logarithm of odds (LOD) score of 4.79 at θ= 0.0 was obtained for several markers. Multipoint linkage analysis resulted in a maximum LOD score of 5.9, which further supports the linkage. Haplotype analysis defined the linkage interval of 17.35 cM flanked by markers D13S325 and D13S1231 according to the Rutgers combined linkage-physical map. This region contains 24.41 Mb according to the build 36 of the human genome sequence-based physical map.
Variegate porphyria (VP; OMIM 176200) is characterized by a partial defect in the activity of pro... more 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.
Cell adhesion and communication are interdependent aspects of cell behavior that are critical for... more Cell adhesion and communication are interdependent aspects of cell behavior that are critical for morphogenesis and tissue architecture. In the skin, epidermal adhesion is mediated in part by specialized cell-cell junctions known as desmosomes, which are characterized by the presence of desmosomal cadherins, known as desmogleins and desmocollins. We identified a cadherin family member, desmoglein 4, which is expressed in the suprabasal epidermis and hair follicle. The essential role of desmoglein 4 in skin was established by identifying mutations in families with inherited hypotrichosis, as well as in the lanceolate hair mouse. We also show that DSG4 is an autoantigen in pemphigus vulgaris. Characterization of the phenotype of naturally occurring mutant mice revealed disruption of desmosomal adhesion and perturbations in keratinocyte behavior. We provide evidence that desmoglein 4 is a key mediator of keratinocyte cell adhesion in the hair follicle, where it coordinates the transition from proliferation to differentiation.
Autosomal recessive hypotrichosis is a rare hereditary disorder characterized by sparse hair on s... more Autosomal recessive hypotrichosis is a rare hereditary disorder characterized by sparse hair on scalp and rest of the body of affected subjects. Recently, three clinically similar autosomal recessive forms of hypotrichosis [localized autosomal recessive hypotrichosis (LAH)1], LAH2 and LAH3 have been mapped on chromosomes 18q12.1, 3q27.3, and 13q14.11-q21.32, respectively. For these three loci, two genes DSG4 for LAH1 and LIPH for LAH2 have been identified. To date, only five mutations in DSG4 and two in LIPH genes have been reported. In this study, we have ascertained two large unrelated consanguineous Pakistani families with autosomal recessive form of hypotrichosis. Affected individuals showed homozygosity to the microsatellite markers tightly linked to LIPH gene on chromosome 3q27. Sequence analysis of the gene in the affected subjects from both the families revealed a novel deletion mutation in exon 5 (c.659-660delTA) causing frameshift and downstream premature termination codon. All the three mutations identified in the LIPH gene, including the one in this study, are deletion mutations.
Abstract: Congenital atrichia with papular lesions is a rare, recessively inherited form of hair ... more Abstract: 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.
Variegate porphyria (VP; OMIM 176200) is characterized by a partial defect in the activity of pro... more 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.
The hairless and rhino mutations are autosomal recessive allelic mutations that map to mouse Chro... more The hairless and rhino mutations are autosomal recessive allelic mutations that map to mouse Chromosome 14. In general, the rhino phenotype is a more severe manifestation of the hairless phenotype. In both hairless and rhino mice, the hair begins shedding in a cephalocaudal pattern within 7 days after birth, and never regrows due to a series of irreversible cellular events. The hairless mutation closely resembles the human disease known as papular atrichia (MIM 209500). Recently, this disease was linked to Chromosome 8p12, the human homolog of hairless was cloned and mapped to the same locus, and mutations have been identified in several different families. In order to gain insight into the pathophysiology of disease in papular atrichia, we sought to utilize mouse mutations as in vivo model systems. In this study, we report the identification of a homozygous nonsense mutation in the coding region of the hr gene in a hairless mouse captured on a chicken farm in the Midwestern United States. To reflect the place of identification of this new mutation at the hr locus, we have designated this allele hrrhChr using the laboratory code Chr (Christiano).
The recent discovery of the human counterpart of the hairless mouse phenotype 1 has helped our un... more The recent discovery of the human counterpart of the hairless mouse phenotype 1 has helped our understanding of the molecular genetics of hair growth. But there are no reports of a defect in the human homologue of the best known of the 'bald' mouse phenotypes, the nude ...
The human desmoglein genes, desmogleins 1--3, are members of the desmosomal cadherin superfamily,... more The human desmoglein genes, desmogleins 1--3, are members of the desmosomal cadherin superfamily, and encode critical components of the desmosome. These genes are tightly clustered within 150--200 kb of chromosome 18q12.1 and represent excellent candidate genes for genetic disorders of the epidermis linked to this region of the genome. Mutations in desmoglein 1 have already been implicated in the genetic disorder striate palmoplantar keratoderma. Similarly, a mutation in desmoglein 3 underlies the balding mouse phenotype, although no human mutations in desmoglein 3 have been identified to date. In this study, we have characterized the genomic organization of two of the three desmoglein genes mapped to chromosome 18q12. Comparison of their exon-intron structure reveals the high level of evolutionary conservation expected from these related genes. The identification of the genomic structure of the desmoglein genes will facilitate mutation detection in genodermatoses with desmosomal abnormalities resulting from underlying defects in these genes.
The present authors have previously described a consanguineous Pakistani family with fibular hypo... more The present authors have previously described a consanguineous Pakistani family with fibular hypoplasia and complex brachydactyly (DuPan syndrome) inherited as an autosomal recessive trait. All affected individuals showed either reductions or absence of bones in the limbs, and appendicular bone dysmorphogenesis with unaffected axial bones. Obligate heterozygote parents were phenotypically normal. Mutations in the cartilage-derived morphogenetic protein 1 (CDMP1) gene have been reported in two acromesomelic chondrodysplasias (i.e. Hunter–Thompson type and Grebe type) which are phenotypically related to DuPan syndrome. CDMP1, a member of the transforming growth factor β super-family of secreted signalling molecules, has been reported to regulate limb patterning and distal bone growth. Therefore, the present authors examined genomic DNA from the family with DuPan syndrome for mutations in the CDMP1 gene. Affected individuals were homozygous for a missense mutation, T1322C, in the coding region of the CDMP1 gene. This mutation was not found in 44 control subjects of Pakistani origin. The T1322C change predicts a leu441pro substitution in the mature domain of the CDMP1 protein. This is likely to cause a conformational change in the CDMP1 protein that influences the expression of genes which are required for normal bone development. This finding extends the spectrum of phenotypes produced by defects in the CDMP1 gene.
Autosomal recessive hypotrichosis is a rare form of alopecia characterized by sparse hair on scal... more Autosomal recessive hypotrichosis is a rare form of alopecia characterized by sparse hair on scalp, sparse to absent eyebrows and eyelashes, and sparse auxiliary and body hair. Previously, for this form of hypotrichosis, two loci LAH (localized hereditary hypotrichosis) and AH (autosomal recessive hereditary hypotrichosis) have been mapped on chromosome 18q12.1 and 3q27.2, respectively. In the study presented here, we report the localization of a third locus for autosomal recessive form of hypotrichosis in two large Pakistani families. The patients in the two families exhibited typical features of the hereditary hypotrichosis. Genome scan using polymorphic microsatellite markers mapped the gene on chromosome 13q14.11–q21.32. A maximum combined two-point logarithm of odds (LOD) score of 4.79 at θ= 0.0 was obtained for several markers. Multipoint linkage analysis resulted in a maximum LOD score of 5.9, which further supports the linkage. Haplotype analysis defined the linkage interval of 17.35 cM flanked by markers D13S325 and D13S1231 according to the Rutgers combined linkage-physical map. This region contains 24.41 Mb according to the build 36 of the human genome sequence-based physical map.
Variegate porphyria (VP; OMIM 176200) is characterized by a partial defect in the activity of pro... more 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.
Cell adhesion and communication are interdependent aspects of cell behavior that are critical for... more Cell adhesion and communication are interdependent aspects of cell behavior that are critical for morphogenesis and tissue architecture. In the skin, epidermal adhesion is mediated in part by specialized cell-cell junctions known as desmosomes, which are characterized by the presence of desmosomal cadherins, known as desmogleins and desmocollins. We identified a cadherin family member, desmoglein 4, which is expressed in the suprabasal epidermis and hair follicle. The essential role of desmoglein 4 in skin was established by identifying mutations in families with inherited hypotrichosis, as well as in the lanceolate hair mouse. We also show that DSG4 is an autoantigen in pemphigus vulgaris. Characterization of the phenotype of naturally occurring mutant mice revealed disruption of desmosomal adhesion and perturbations in keratinocyte behavior. We provide evidence that desmoglein 4 is a key mediator of keratinocyte cell adhesion in the hair follicle, where it coordinates the transition from proliferation to differentiation.
Autosomal recessive hypotrichosis is a rare hereditary disorder characterized by sparse hair on s... more Autosomal recessive hypotrichosis is a rare hereditary disorder characterized by sparse hair on scalp and rest of the body of affected subjects. Recently, three clinically similar autosomal recessive forms of hypotrichosis [localized autosomal recessive hypotrichosis (LAH)1], LAH2 and LAH3 have been mapped on chromosomes 18q12.1, 3q27.3, and 13q14.11-q21.32, respectively. For these three loci, two genes DSG4 for LAH1 and LIPH for LAH2 have been identified. To date, only five mutations in DSG4 and two in LIPH genes have been reported. In this study, we have ascertained two large unrelated consanguineous Pakistani families with autosomal recessive form of hypotrichosis. Affected individuals showed homozygosity to the microsatellite markers tightly linked to LIPH gene on chromosome 3q27. Sequence analysis of the gene in the affected subjects from both the families revealed a novel deletion mutation in exon 5 (c.659-660delTA) causing frameshift and downstream premature termination codon. All the three mutations identified in the LIPH gene, including the one in this study, are deletion mutations.
Abstract: Congenital atrichia with papular lesions is a rare, recessively inherited form of hair ... more Abstract: 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.
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Papers by Wasim Ahmad