Peter Byers - Academia.edu (original) (raw)
Papers by Peter Byers
Journal of Medical Genetics, Feb 1, 2002
ObjectivesTranscript sequencing of patient derived samples has been shown to improve the diagnost... more ObjectivesTranscript sequencing of patient derived samples has been shown to improve the diagnostic yield for solving cases of likely Mendelian disorders, yet the added benefit of full-length long-read transcript sequencing is largely unexplored.MethodsWe applied short-read and full-length isoform cDNA sequencing and mitochondrial functional studies to a patient-derived fibroblast cell line from an individual with neuropathy that previously lacked a molecular diagnosis.ResultsWe identified an intronic homozygousMFN2c.600-31T>G variant that disrupts a branch point critical for intron 6 spicing. Full-length long-read isoform cDNA sequencing after treatment with a nonsense-mediated mRNA decay (NMD) inhibitor revealed that this variant creates five distinct altered splicing transcripts. All five altered splicing transcripts have disrupted open reading frames and are subject to NMD. Furthermore, a patient-derived fibroblast line demonstrated abnormal lipid droplet formation, consisten...
The American journal of pathology, 1993
Bovine Marfan syndrome is a disorder that closely resembles human Marfan syndrome in its clinical... more Bovine Marfan syndrome is a disorder that closely resembles human Marfan syndrome in its clinical signs and pathological lesions. The similarities between the human and bovine diseases suggest that similar metabolic defects could be responsible. Although indirect immunofluorescent assays for fibrillin in skin biopsies did not distinguish affected cattle from control animals, cultures of skin fibroblasts of affected animals were distinguished from normal, unrelated control animals and normal half-siblings on the basis of fibrillin staining. After 72 to 96 hours in culture, stained with anti-fibrillin monoclonal antibody 201, hyperconfluent fibroblast cultures of affected cattle had less immunoreactive fibrillin than control cultures, and the staining pattern was granular rather than fibrillar. Under similar culture conditions, normal bovine aortic smooth muscle cells produced large amounts of immunoreactive fibrillin, but smooth muscle cells from a single affected cow showed markedly...
Transactions of the American Clinical and Climatological Association, 1974
Proceedings of the National Academy of Sciences, 1981
Cells in culture from a woman with a variety of the Marfan syndrome produce two species of the al... more Cells in culture from a woman with a variety of the Marfan syndrome produce two species of the alpha 2 chains of type I collagen. One alpha 2 chain appears normal; the abnormal chain has a higher apparent molecular weight than normal and migrates more slowly during electrophoresis in sodium dodecyl sulfate/polyacrylamide gels. A similar change in electrophoretic behavior is seen in the prepro alpha 2 chain and the pN alpha 2 chain (which contains the amino-terminal extension). Asymmetric cleavage of the pepsin-treated procollagens with a fibroblast collagenase locates the abnormal segment amino terminal to the cleavage site, and analysis of cyanogen bromide peptides of collagenase cleavage peptides and of whole collagens indicates that the abnormal segment is in either the alpha 2CB3 peptide or the short segment of alpha 2CB5 amino terminal to the collagenase site of the altered alpha 2 chain. The higher apparent molecular weight is consistent with the insertion of a small peptide f...
Journal of Investigative Dermatology, 1982
Clinical characteristics Vascular Ehlers-Danlos syndrome (vEDS) is characterized by arterial, int... more Clinical characteristics Vascular Ehlers-Danlos syndrome (vEDS) is characterized by arterial, intestinal, and/or uterine fragility; thin, translucent skin; easy bruising; characteristic facial appearance (thin vermilion of the lips, micrognathia, narrow nose, prominent eyes); and an aged appearance to the extremities, particularly the hands. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in most adults with vEDS. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously. The majority (60%) of individuals with vEDS who are diagnosed before age 18 years are identified because of a positive family history. Neonates may present with clubfoot, hip dislocation, limb deficiency, and/or amniotic bands. Approximately half of children tested for vEDS in the absence of a positive family history present with a major complication at an average age of 11 years. Four minor diagnostic...
Summary Dermatosparaxis isa recessively inherited connective-tissue disorder that results fromlac... more Summary Dermatosparaxis isa recessively inherited connective-tissue disorder that results fromlack oftheactivity of typeIprocollagen N-proteinase, the enzyme that removes theamino-terminal propeptides fromtypeI procollagen. Initially identified incattle more than20yearsago,thedisorder was subsequently characterized insheep, cats,anddogs. Affected animals havefragile skin, laxjoints, andoften dieprematurely because ofsepsis following avulsion ofportions ofskin. Werecently identified twochildren withsoft, lax, andfragile skin, which, whenexamined bytransmission electron microscopy, contained thetwisted, ribbon-like collagenfibrils characteristic ofdermatosparaxis. Skin extracts fromone child contained collagen precursorswith amino-terminal extensions. Cultured fibroblasts frombothchildren failed tocleave theamino-terminal propeptides fromtheproal(I) andproa2(I) chains intypeIprocollagen molecules. Extracts ofnormal cells cleaved tocollagen, thetypeIprocollagen synthesized bycells from...
European Journal of Human Genetics, 2021
The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for... more The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3–5). It identified ‘mutational hotspots’ (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that ‘well-established’ functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to conf...
American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 2017
Since 1998, two developments have led to concerns that the EDS nosology needs to be substantially... more Since 1998, two developments have led to concerns that the EDS nosology needs to be substantially revised. The first development was the clinical and molecular characterization of several new EDS variants, which substantially broadened the molecular basis underlying EDS. The second was the growing concern, in the absence of genetic diagnosis, that the hypermobile type of EDS had an expanded phenotype, may be genetically heterogeneous, and that the diagnostic criteria currently in use were inadequate. Furthermore, there is a dire need for the development of guidelines for management for each type of EDS to allow both the specialist and the generalist to care for affected individuals and their families. We have been meeting together as an international consortium over the past 2 years to establish these new criteria and management and care guidelines © 2017 Wiley Periodicals, Inc.
The American Journal of Human Genetics, 2015
Genome research, Jan 30, 2015
Recommendations for laboratories to report incidental findings from genomic tests have stimulated... more Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected ...
Rheumatology, 2011
NFC and median duration of cGvHD before NFC was much shorter in their patient group (3 vs 30 mont... more NFC and median duration of cGvHD before NFC was much shorter in their patient group (3 vs 30 months). Fleming et al. [4] noted areas of microvascular proliferations in some cGvHD biopsies, especially in those with a lichenoid histological picture. We do not know whether the NFC abnormalities described by Akay et al. were different between patients with lichenoid changes (nine in Akay's report) or not, but we did not observe any NFC abnormalities in our patients with lichenoid changes. Furthermore, these authors used dermatoscopy-a method that showed inferior reliability in patients with SSc compared with standard NFC [7]. This fact may have additionally contributed to the different interpretation of the capillary morphology. On the other hand, our findings support those of Fleming et al. [4] who could demonstrate by histopathology only slight alterations in superficial dermal microvessels in cGvHD in contrast to patients with SSc, in whom capillaries were significantly reduced in number, showed fewer canonical endothelial markers and no microvascular endothelial proliferation. In summary, our results further support the hypothesis that cGvHD of the skin and SSc are two similar-looking phenomena of skin fibrosis, but with a different pathophysiology, and therefore may need different therapeutic approaches. Thus, cGvHD patients and pathological findings on NFC may represent a different group and should be carefully evaluated for new-onset collagenosis. Rheumatology key message. Patients with cGvHD of the skin after HCST present normal nail-fold capillary findings.
Proceedings of the National Academy of Sciences, 1981
Osteogenesis imperfecta is a clinically and genetically heterogeneous group of inherited connecti... more Osteogenesis imperfecta is a clinically and genetically heterogeneous group of inherited connective tissue disorders in which bone fragility is the predominant feature. Cultured dermal fibroblasts from one patient with the lethal perinatal form of osteogenesis imperfecta secrete type I procollagen at a rate half that of normal cells. Short-term labeling experiments and treatment with alpha,alpha'-dipyridyl (which prevents posttranslational prolyl and lysyl hydroxylation) demonstrated that these cells produce two distinct pro alpha 1(I) chains, which are synthesized at the same rate. Analysis of cyanogen bromide peptides indicated that the two chains differ in their primary structures. Thus, structural abnormalities in type I procollagen prevent this molecule from being secreted normally, resulting in an anomalously low ratio of type I procollagen to other extracellular matrix molecules. While the lethal perinatal form of osteogenesis imperfecta may be heterogeneous, we propose t...
Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 2001
Fibrillar collagens have a long triple helix in which glycine is in every third position for more... more Fibrillar collagens have a long triple helix in which glycine is in every third position for more than 1000 amino acids. The three chains of these molecules are assembled with specificity into several different molecules that have tissue–specific distribution. Mutations that alter folding of either the carboxy–terminal globular peptides that direct chain association, or of the regions of the triple helix that are important for nucleation, or of the bulk of the triple helix, all result in identifiable genetic disorders in which the phenotype reflects the region of expression of the genes and their tissue–specific distribution. Mutations that result in changed amino–acid sequences in any of these regions have different effects on folding and may have different phenotypic outcomes. Substitution for glycine residues in the triple helical domains are among the most common effects of mutations, and the nature of the substituting residue and its location in the chain contribute to the effe...
Journal of Medical Genetics, 1989
Single base pair alterations as the predominant category of mutation in type I osteogenesis imper... more Single base pair alterations as the predominant category of mutation in type I osteogenesis imperfecta
Journal of Investigative Dermatology, 1989
Cutis laxa is a genetically heterogeneous connective tissue disease that occurs in both inherited... more Cutis laxa is a genetically heterogeneous connective tissue disease that occurs in both inherited and acquired forms. The most apparent defect is loose, redundant, nonresilient skin, but systemic cOlU1ective tissue abnormalities exist, especially in conjunction with the early onset or autosomal recessive variety. The elastic fiber shows morphologic alterations. We studied dermal skin biopsies and cultured skin fibroblasts from 6 patients with congenital forms of cutis laxa in an effort to correlate alterations in elastin morphology and metabolism. In general, ultrastructural analysis revealed occasional variance in collagen fiber diameter, whereas elastic tissue varied in content, appearance, and the proportion and manner by which elastin and microfibrillar component associated. Fibroblast cell lines comprised of normal donors from C utis laxa is one of a variety of clinically and genetically heterogeneous connective tissue diseases and may be acquired or inherited in a dominant [1,2] or an autosomal recessive [1,3-5] manner. Although clinical distinctions are not precise, in general the autosoma l dominant form is less severe with late onset of dermal laxity and rare involvement of organs. The autosomal recessive disease is usuall y present at birth and is characterized by extreme skin laxity and systemic involvement. Acquired forms of the disease often exist as a complication of an inflammatory episode [6-9]. An X-linked form Manuscript
Journal of Investigative Dermatology, 1980
FIG 6. TEM of epidermis (Ep) and papillary dermis from the dermatosparactic cat. (a) Elastic conn... more FIG 6. TEM of epidermis (Ep) and papillary dermis from the dermatosparactic cat. (a) Elastic connective tissue (E) is particularly abundant in this region and is mixed with collagen fibrils which are nearly normal in structure (b) (X 8000; X 14,000). in the sheep and the more benign but disabling disorder of man. Although only a small proportion of the a-chains in skin retain NHz-terminal extensions there are alterations in collagen fibril structure, in the organization of fibrils into fibers and fiber Vol. 74, No.2 bundles, in the integration of bundles in the dermis and fmally, in the mechanical properties of skin. We wish to thank Mrs. Mary Hoff for her excellent technical assistance, Mr. Tim J. Moore for the scanning electron micrograph in Fig 2b, Ms. Dads Ringer for preparation of the manuscript and Drs. George F. Odland, Paul Bornstein and Gary Striker for their support and encouragement of this work.
Journal of Clinical Investigation, 2004
Nonstandard abbreviations used: angiotensin II (ATII); familial partial lipodystrophy type 3 (FPL... more Nonstandard abbreviations used: angiotensin II (ATII); familial partial lipodystrophy type 3 (FPLD3); metabolic syndrome (MetS); renin-angiotensin system (RAS); type 2 diabetes mellitus (T2DM).
Journal of Medical Genetics, Feb 1, 2002
ObjectivesTranscript sequencing of patient derived samples has been shown to improve the diagnost... more ObjectivesTranscript sequencing of patient derived samples has been shown to improve the diagnostic yield for solving cases of likely Mendelian disorders, yet the added benefit of full-length long-read transcript sequencing is largely unexplored.MethodsWe applied short-read and full-length isoform cDNA sequencing and mitochondrial functional studies to a patient-derived fibroblast cell line from an individual with neuropathy that previously lacked a molecular diagnosis.ResultsWe identified an intronic homozygousMFN2c.600-31T>G variant that disrupts a branch point critical for intron 6 spicing. Full-length long-read isoform cDNA sequencing after treatment with a nonsense-mediated mRNA decay (NMD) inhibitor revealed that this variant creates five distinct altered splicing transcripts. All five altered splicing transcripts have disrupted open reading frames and are subject to NMD. Furthermore, a patient-derived fibroblast line demonstrated abnormal lipid droplet formation, consisten...
The American journal of pathology, 1993
Bovine Marfan syndrome is a disorder that closely resembles human Marfan syndrome in its clinical... more Bovine Marfan syndrome is a disorder that closely resembles human Marfan syndrome in its clinical signs and pathological lesions. The similarities between the human and bovine diseases suggest that similar metabolic defects could be responsible. Although indirect immunofluorescent assays for fibrillin in skin biopsies did not distinguish affected cattle from control animals, cultures of skin fibroblasts of affected animals were distinguished from normal, unrelated control animals and normal half-siblings on the basis of fibrillin staining. After 72 to 96 hours in culture, stained with anti-fibrillin monoclonal antibody 201, hyperconfluent fibroblast cultures of affected cattle had less immunoreactive fibrillin than control cultures, and the staining pattern was granular rather than fibrillar. Under similar culture conditions, normal bovine aortic smooth muscle cells produced large amounts of immunoreactive fibrillin, but smooth muscle cells from a single affected cow showed markedly...
Transactions of the American Clinical and Climatological Association, 1974
Proceedings of the National Academy of Sciences, 1981
Cells in culture from a woman with a variety of the Marfan syndrome produce two species of the al... more Cells in culture from a woman with a variety of the Marfan syndrome produce two species of the alpha 2 chains of type I collagen. One alpha 2 chain appears normal; the abnormal chain has a higher apparent molecular weight than normal and migrates more slowly during electrophoresis in sodium dodecyl sulfate/polyacrylamide gels. A similar change in electrophoretic behavior is seen in the prepro alpha 2 chain and the pN alpha 2 chain (which contains the amino-terminal extension). Asymmetric cleavage of the pepsin-treated procollagens with a fibroblast collagenase locates the abnormal segment amino terminal to the cleavage site, and analysis of cyanogen bromide peptides of collagenase cleavage peptides and of whole collagens indicates that the abnormal segment is in either the alpha 2CB3 peptide or the short segment of alpha 2CB5 amino terminal to the collagenase site of the altered alpha 2 chain. The higher apparent molecular weight is consistent with the insertion of a small peptide f...
Journal of Investigative Dermatology, 1982
Clinical characteristics Vascular Ehlers-Danlos syndrome (vEDS) is characterized by arterial, int... more Clinical characteristics Vascular Ehlers-Danlos syndrome (vEDS) is characterized by arterial, intestinal, and/or uterine fragility; thin, translucent skin; easy bruising; characteristic facial appearance (thin vermilion of the lips, micrognathia, narrow nose, prominent eyes); and an aged appearance to the extremities, particularly the hands. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in most adults with vEDS. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously. The majority (60%) of individuals with vEDS who are diagnosed before age 18 years are identified because of a positive family history. Neonates may present with clubfoot, hip dislocation, limb deficiency, and/or amniotic bands. Approximately half of children tested for vEDS in the absence of a positive family history present with a major complication at an average age of 11 years. Four minor diagnostic...
Summary Dermatosparaxis isa recessively inherited connective-tissue disorder that results fromlac... more Summary Dermatosparaxis isa recessively inherited connective-tissue disorder that results fromlack oftheactivity of typeIprocollagen N-proteinase, the enzyme that removes theamino-terminal propeptides fromtypeI procollagen. Initially identified incattle more than20yearsago,thedisorder was subsequently characterized insheep, cats,anddogs. Affected animals havefragile skin, laxjoints, andoften dieprematurely because ofsepsis following avulsion ofportions ofskin. Werecently identified twochildren withsoft, lax, andfragile skin, which, whenexamined bytransmission electron microscopy, contained thetwisted, ribbon-like collagenfibrils characteristic ofdermatosparaxis. Skin extracts fromone child contained collagen precursorswith amino-terminal extensions. Cultured fibroblasts frombothchildren failed tocleave theamino-terminal propeptides fromtheproal(I) andproa2(I) chains intypeIprocollagen molecules. Extracts ofnormal cells cleaved tocollagen, thetypeIprocollagen synthesized bycells from...
European Journal of Human Genetics, 2021
The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for... more The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3–5). It identified ‘mutational hotspots’ (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that ‘well-established’ functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to conf...
American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 2017
Since 1998, two developments have led to concerns that the EDS nosology needs to be substantially... more Since 1998, two developments have led to concerns that the EDS nosology needs to be substantially revised. The first development was the clinical and molecular characterization of several new EDS variants, which substantially broadened the molecular basis underlying EDS. The second was the growing concern, in the absence of genetic diagnosis, that the hypermobile type of EDS had an expanded phenotype, may be genetically heterogeneous, and that the diagnostic criteria currently in use were inadequate. Furthermore, there is a dire need for the development of guidelines for management for each type of EDS to allow both the specialist and the generalist to care for affected individuals and their families. We have been meeting together as an international consortium over the past 2 years to establish these new criteria and management and care guidelines © 2017 Wiley Periodicals, Inc.
The American Journal of Human Genetics, 2015
Genome research, Jan 30, 2015
Recommendations for laboratories to report incidental findings from genomic tests have stimulated... more Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected ...
Rheumatology, 2011
NFC and median duration of cGvHD before NFC was much shorter in their patient group (3 vs 30 mont... more NFC and median duration of cGvHD before NFC was much shorter in their patient group (3 vs 30 months). Fleming et al. [4] noted areas of microvascular proliferations in some cGvHD biopsies, especially in those with a lichenoid histological picture. We do not know whether the NFC abnormalities described by Akay et al. were different between patients with lichenoid changes (nine in Akay's report) or not, but we did not observe any NFC abnormalities in our patients with lichenoid changes. Furthermore, these authors used dermatoscopy-a method that showed inferior reliability in patients with SSc compared with standard NFC [7]. This fact may have additionally contributed to the different interpretation of the capillary morphology. On the other hand, our findings support those of Fleming et al. [4] who could demonstrate by histopathology only slight alterations in superficial dermal microvessels in cGvHD in contrast to patients with SSc, in whom capillaries were significantly reduced in number, showed fewer canonical endothelial markers and no microvascular endothelial proliferation. In summary, our results further support the hypothesis that cGvHD of the skin and SSc are two similar-looking phenomena of skin fibrosis, but with a different pathophysiology, and therefore may need different therapeutic approaches. Thus, cGvHD patients and pathological findings on NFC may represent a different group and should be carefully evaluated for new-onset collagenosis. Rheumatology key message. Patients with cGvHD of the skin after HCST present normal nail-fold capillary findings.
Proceedings of the National Academy of Sciences, 1981
Osteogenesis imperfecta is a clinically and genetically heterogeneous group of inherited connecti... more Osteogenesis imperfecta is a clinically and genetically heterogeneous group of inherited connective tissue disorders in which bone fragility is the predominant feature. Cultured dermal fibroblasts from one patient with the lethal perinatal form of osteogenesis imperfecta secrete type I procollagen at a rate half that of normal cells. Short-term labeling experiments and treatment with alpha,alpha'-dipyridyl (which prevents posttranslational prolyl and lysyl hydroxylation) demonstrated that these cells produce two distinct pro alpha 1(I) chains, which are synthesized at the same rate. Analysis of cyanogen bromide peptides indicated that the two chains differ in their primary structures. Thus, structural abnormalities in type I procollagen prevent this molecule from being secreted normally, resulting in an anomalously low ratio of type I procollagen to other extracellular matrix molecules. While the lethal perinatal form of osteogenesis imperfecta may be heterogeneous, we propose t...
Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 2001
Fibrillar collagens have a long triple helix in which glycine is in every third position for more... more Fibrillar collagens have a long triple helix in which glycine is in every third position for more than 1000 amino acids. The three chains of these molecules are assembled with specificity into several different molecules that have tissue–specific distribution. Mutations that alter folding of either the carboxy–terminal globular peptides that direct chain association, or of the regions of the triple helix that are important for nucleation, or of the bulk of the triple helix, all result in identifiable genetic disorders in which the phenotype reflects the region of expression of the genes and their tissue–specific distribution. Mutations that result in changed amino–acid sequences in any of these regions have different effects on folding and may have different phenotypic outcomes. Substitution for glycine residues in the triple helical domains are among the most common effects of mutations, and the nature of the substituting residue and its location in the chain contribute to the effe...
Journal of Medical Genetics, 1989
Single base pair alterations as the predominant category of mutation in type I osteogenesis imper... more Single base pair alterations as the predominant category of mutation in type I osteogenesis imperfecta
Journal of Investigative Dermatology, 1989
Cutis laxa is a genetically heterogeneous connective tissue disease that occurs in both inherited... more Cutis laxa is a genetically heterogeneous connective tissue disease that occurs in both inherited and acquired forms. The most apparent defect is loose, redundant, nonresilient skin, but systemic cOlU1ective tissue abnormalities exist, especially in conjunction with the early onset or autosomal recessive variety. The elastic fiber shows morphologic alterations. We studied dermal skin biopsies and cultured skin fibroblasts from 6 patients with congenital forms of cutis laxa in an effort to correlate alterations in elastin morphology and metabolism. In general, ultrastructural analysis revealed occasional variance in collagen fiber diameter, whereas elastic tissue varied in content, appearance, and the proportion and manner by which elastin and microfibrillar component associated. Fibroblast cell lines comprised of normal donors from C utis laxa is one of a variety of clinically and genetically heterogeneous connective tissue diseases and may be acquired or inherited in a dominant [1,2] or an autosomal recessive [1,3-5] manner. Although clinical distinctions are not precise, in general the autosoma l dominant form is less severe with late onset of dermal laxity and rare involvement of organs. The autosomal recessive disease is usuall y present at birth and is characterized by extreme skin laxity and systemic involvement. Acquired forms of the disease often exist as a complication of an inflammatory episode [6-9]. An X-linked form Manuscript
Journal of Investigative Dermatology, 1980
FIG 6. TEM of epidermis (Ep) and papillary dermis from the dermatosparactic cat. (a) Elastic conn... more FIG 6. TEM of epidermis (Ep) and papillary dermis from the dermatosparactic cat. (a) Elastic connective tissue (E) is particularly abundant in this region and is mixed with collagen fibrils which are nearly normal in structure (b) (X 8000; X 14,000). in the sheep and the more benign but disabling disorder of man. Although only a small proportion of the a-chains in skin retain NHz-terminal extensions there are alterations in collagen fibril structure, in the organization of fibrils into fibers and fiber Vol. 74, No.2 bundles, in the integration of bundles in the dermis and fmally, in the mechanical properties of skin. We wish to thank Mrs. Mary Hoff for her excellent technical assistance, Mr. Tim J. Moore for the scanning electron micrograph in Fig 2b, Ms. Dads Ringer for preparation of the manuscript and Drs. George F. Odland, Paul Bornstein and Gary Striker for their support and encouragement of this work.
Journal of Clinical Investigation, 2004
Nonstandard abbreviations used: angiotensin II (ATII); familial partial lipodystrophy type 3 (FPL... more Nonstandard abbreviations used: angiotensin II (ATII); familial partial lipodystrophy type 3 (FPLD3); metabolic syndrome (MetS); renin-angiotensin system (RAS); type 2 diabetes mellitus (T2DM).