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Clinical Journal of the American... Nov 2022Digenic Alport syndrome refers to the inheritance of pathogenic variants in plus or or in plus Where digenic Alport syndrome includes a pathogenic variant, the... (Review)
Review
Digenic Alport syndrome refers to the inheritance of pathogenic variants in plus or or in plus Where digenic Alport syndrome includes a pathogenic variant, the consequences depend on the sex of the affected individual, variant "severity," and the nature of the or change. A man with a pathogenic variant has all his collagen IV 345-heterotrimers affected, and an additional or variant may not worsen disease. A woman with a pathogenic variant has on average 50% of her heterotrimers affected, which is increased to 75% with a further or variant and associated with a higher risk of proteinuria. In digenic Alport syndrome with pathogenic and variants, 75% of the heterotrimers are affected. The and genes occur head-to-head on chromosome 2, and inheritance is autosomal dominant when both variants affect the same chromosome () or recessive when they affect different chromosomes (). This form of digenic disease results in increased proteinuria and a median age of kidney failure intermediate between autosomal dominant and autosomal recessive Alport syndrome. Previous guidelines have suggested that all pathogenic or likely pathogenic digenic variants should be identified and reported. Affected family members should be identified, treated, and discouraged from kidney donation. Inheritance within a family is easier to predict if the two variants are considered independently and if and variants are known to be inherited on the same or different chromosomes.
Topics: Humans; Male; Female; Nephritis, Hereditary; Pedigree; Autoantigens; Collagen Type IV; Proteinuria; Mutation
PubMed: 35675912
DOI: 10.2215/CJN.03120322 -
Genetics in Medicine : Official Journal... Oct 2010Classic Ehlers-Danlos syndrome is a heritable connective tissue disorder characterized by skin hyperextensibility, fragile and soft skin, delayed wound healing with... (Review)
Review
Classic Ehlers-Danlos syndrome is a heritable connective tissue disorder characterized by skin hyperextensibility, fragile and soft skin, delayed wound healing with formation of atrophic scars, easy bruising, and generalized joint hypermobility. It comprises Ehlers-Danlos syndrome type I and Ehlers-Danlos syndrome type II, but it is now apparent that these form a continuum of clinical findings and differ only in phenotypic severity. It is currently estimated that approximately 50% of patients with a clinical diagnosis of classic Ehlers-Danlos syndrome harbor mutations in the COL5A1 and the COL5A2 gene, encoding the α1 and the α2-chain of type V collagen, respectively. However, because no prospective molecular studies of COL5A1 and COL5A2 have been performed in a clinically well-defined patient group, this number may underestimate the real proportion of patients with classic Ehlers-Danlos syndrome harboring a mutation in one of these genes. In the majority of patients with molecularly characterized classic Ehlers-Danlos syndrome, the disease is caused by a mutation leading to a nonfunctional COL5A1 allele and resulting in haploinsufficiency of type V collagen. A smaller proportion of patients harbor a structural mutation in COL5A1 or COL5A2, causing the production of a functionally defective type V collagen protein. Most mutations identified so far result in a reduced amount of type V collagen in the connective tissues available for collagen fibrillogenesis. Inter- and intrafamilial phenotypic variability is observed, but no genotype-phenotype correlations have been observed. No treatment for the underlying defect is presently available for Ehlers-Danlos syndrome. However, a series of preventive guidelines are applicable.
Topics: Collagen Type V; Connective Tissue; Contusions; Ehlers-Danlos Syndrome; Genotype; Haploinsufficiency; Humans; Joint Instability; Mutation; Phenotype
PubMed: 20847697
DOI: 10.1097/GIM.0b013e3181eed412 -
European Journal of Human Genetics :... Jul 2019Osteogenesis imperfecta (OI) is a rare genetic disorder of the connective tissue and 90% of cases are due to dominant mutations in COL1A1 and COL1A2 genes. To increase... (Clinical Trial)
Clinical Trial
Osteogenesis imperfecta (OI) is a rare genetic disorder of the connective tissue and 90% of cases are due to dominant mutations in COL1A1 and COL1A2 genes. To increase OI disease knowledge and contribute to patient follow-up management, a homogeneous Italian cohort of 364 subjects affected by OI types I-IV was evaluated. The study population was composed of 262 OI type I, 24 type II, 39 type III, and 39 type IV patients. Three hundred and nine subjects had a type I collagen affecting function mutations (230 in α1(I) and 79 in α2(I)); no disease-causing changes were noticed in 55 patients. Compared with previous genotype-phenotype OI correlation studies, additional observations arose: a new effect for α1- and α2-serine substitutions has been pointed out and heart defects, never considered before, resulted associated to quantitative mutations (P = 0.043). Moreover, some different findings emerged if compared with previous literature; especially, focusing the attention on the lethal form, no association with specific collagen regions was found and most of variants localized in the previously reported "lethal clusters" were causative of OI types I-IV. Some discrepancies have been highlighted also considering the "50-55 nucleotides rule," as well as the relationship between specific collagen I mutated region and the presence of dentinogenesis imperfecta and/or blue sclera. Despite difficulties still present in defining clear rules to predict the clinical outcome in OI patients, this study provides new pieces for completing the puzzle, also thanks to the inclusion of clinical signs never considered before and to the large number of OI Italian patients.
Topics: Adult; Amino Acid Substitution; Child, Preschool; Collagen Type I; Collagen Type I, alpha 1 Chain; Female; Genotype; Humans; Infant; Italy; Male; Mutation, Missense; Osteogenesis Imperfecta; Phenotype; Young Adult
PubMed: 30886339
DOI: 10.1038/s41431-019-0373-x -
Matrix Biology : Journal of the... Apr 2016Keloids, fibroproliferative dermal tumors with effusive accumulation of extracellular matrix (ECM) components, particularly collagen, result from excessive expression of... (Review)
Review
Keloids, fibroproliferative dermal tumors with effusive accumulation of extracellular matrix (ECM) components, particularly collagen, result from excessive expression of growth factors and cytokines. The etiology of keloids is unknown but they occur after dermal injury in genetically susceptible individuals, and they cause both physical and psychological distress for the affected individuals. Several treatment methods for keloids exist, including the combination therapy of surgical excision followed by intralesional steroid therapy, however, they have high recurrence rate regardless of the current treatment method. Improved understanding of the pathomechanisms leading to keloid formation will hopefully identify pathways that serve as specific targets to improve therapy for this devastating, currently intractable, disorder.
Topics: Collagen; Extracellular Matrix; Fibroblasts; Fibrosis; Humans; Keloid; Skin; Steroids; Wound Healing
PubMed: 26844756
DOI: 10.1016/j.matbio.2016.01.013 -
Essays in Biochemistry Sep 2019Basement membranes (BMs) are specialised extracellular matrix (ECM) structures and collagens are a key component required for BM function. While collagen IV is the major... (Review)
Review
Basement membranes (BMs) are specialised extracellular matrix (ECM) structures and collagens are a key component required for BM function. While collagen IV is the major BM collagen, collagens VI, VII, XV, XVII and XVIII are also present. Mutations in these collagens cause rare multi-systemic diseases but these collagens have also been associated with major common diseases including stroke. Developing treatments for these conditions will require a collective effort to increase our fundamental understanding of the biology of these collagens and the mechanisms by which mutations therein cause disease. Novel insights into pathomolecular disease mechanisms and cellular responses to these mutations has been exploited to develop proof-of-concept treatment strategies in animal models. Combined, these studies have also highlighted the complexity of the disease mechanisms and the need to obtain a more complete understanding of these mechanisms. The identification of pathomolecular mechanisms of collagen mutations shared between different disorders represent an attractive prospect for treatments that may be effective across phenotypically distinct disorders.
Topics: Animals; Basement Membrane; Collagen Diseases; Genetic Therapy; Humans; Mutation; Non-Fibrillar Collagens
PubMed: 31387942
DOI: 10.1042/EBC20180071 -
Journal Der Deutschen Dermatologischen... Aug 2013Acquired reactive perforating dermatosis is characterized by umbilicated erythematous papules and plaques with firmly adherent crusts. Histopathological examination... (Review)
Review
Acquired reactive perforating dermatosis is characterized by umbilicated erythematous papules and plaques with firmly adherent crusts. Histopathological examination shows a typical cup-shaped ulceration in the epidermis containing cellular debris and collagen. There is transepidermal elimination of degenerated material with basophilic collagen bundles. The etiology and pathogenesis of acquired reactive perforating dermatosis are unclear. Metabolic disorders and malignancies are associated with this dermatosis. Associated pruritus is regarded as a key pathogenic factor. Constant scratching may cause a repetitive trauma to the skin. This pathogenesis may involve a genetic predisposition. The trauma may lead to degeneration of the collagen bundles. Treatment of acquired reactive perforating dermatosis follows a multimodal approach. Apart from the treating any underlying disease, treatment of pruritus is a major goal. Systemic steroids and retinoids, as well as UVB phototherapy are well-established treatment options. Some patients may also benefit from oral allopurinol.
Topics: Allopurinol; Collagen Diseases; Combined Modality Therapy; Diagnosis, Differential; Humans; Immunosuppressive Agents; Retinoids; Skin Diseases, Genetic; Steroids; Ultraviolet Therapy
PubMed: 23718268
DOI: 10.1111/ddg.12131 -
Medicina (Kaunas, Lithuania) 2017The most frequent cause of familial glomerular hematuria is thin basement membrane nephropathy (TBMN) caused by germline COL4A3 or COL4A4 gene mutations. Less frequent... (Review)
Review
The most frequent cause of familial glomerular hematuria is thin basement membrane nephropathy (TBMN) caused by germline COL4A3 or COL4A4 gene mutations. Less frequent but important cause with respect to morbidity is Alport syndrome caused by germline COL4A5 gene mutations. The features of Alport syndrome include hematuria, proteinuria and all males with X-linked disease and all individuals with recessive disease will develop end stage renal disease, usually at early youth. In X-linked Alport syndrome, a clear genotype-phenotype correlation is typically observed in men. Deleterious COL4A5 mutations are associated with a more severe renal phenotype and more frequent high-frequency sensorineural hearing loss and ocular abnormalities. Less severe COL4A5 mutations result in a milder phenotype, with less frequent and later onset extrarenal anomalies. The phenotype in females is highly variable, mostly due to inactivation of one of the X chromosomes. Isolated cases may be caused by de novo COL4A5 mutations or by gonosomal mosaicism. Untreated autosomal recessive Alport syndrome, caused by COL4A3 and COL4A4 mutations, is typically associated with ESRD at the age of 23-25 years and extrarenal symptoms in both men and women. The TBMN phenotype is associated with heterozygous carriers of COL4A3, COL4A4 mutations. Molecular genetic testing is the gold standard for diagnosing these diseases. Although genotype-phenotype correlations exist, the phenotype is influenced by modifying factors, which remain mainly undefined. No therapy is available that targets the cause of Alport syndrome; angiotensin-converting enzyme inhibitor therapy delays renal failure and improves lifespan.
Topics: Adult; Biopsy; Collagen Type IV; Female; Genetic Association Studies; Genetic Diseases, X-Linked; Genetic Predisposition to Disease; Glomerular Basement Membrane; Hematuria; Hemizygote; Humans; Male; Nephritis, Hereditary; Prevalence; Proteinuria; Risk
PubMed: 28236514
DOI: 10.1016/j.medici.2017.01.002 -
Journal of Bone and Mineral Research :... Apr 2016Osteogenesis imperfecta entrains changes at every level in bone tissue, from the disorganization of the collagen molecules and mineral platelets within and between... (Review)
Review
Osteogenesis imperfecta entrains changes at every level in bone tissue, from the disorganization of the collagen molecules and mineral platelets within and between collagen fibrils to the macroarchitecture of the whole skeleton. Investigations using an array of sophisticated instruments at multiple scale levels have now determined many aspects of the effect of the disease on the material properties of bone tissue. The brittle nature of bone in osteogenesis imperfecta reflects both increased bone mineralization density-the quantity of mineral in relation to the quantity of matrix within a specific bone volume-and altered matrix-matrix and matrix mineral interactions. Contributions to fracture resistance at multiple scale lengths are discussed, comparing normal and brittle bone. Integrating the available information provides both a better understanding of the effect of current approaches to treatment-largely improved architecture and possibly some macroscale toughening-and indicates potential opportunities for alternative strategies that can influence fracture resistance at longer-length scales.
Topics: Bone Density; Fractures, Bone; Humans; Osteogenesis Imperfecta
PubMed: 26987995
DOI: 10.1002/jbmr.2835 -
Clinical Journal of the American... Jul 2021The glomerular basement membrane is a vital component of the filtration barrier of the kidney and is primarily composed of a highly structured matrix of type IV... (Review)
Review
The glomerular basement membrane is a vital component of the filtration barrier of the kidney and is primarily composed of a highly structured matrix of type IV collagen. Specific isoforms of type IV collagen, the 3(IV), 4(IV), and 5(IV) isoforms, assemble into trimers that are required for normal glomerular basement membrane function. Disruption or alteration in these isoforms leads to breakdown of the glomerular basement membrane structure and function and can lead to progressive CKD known as Alport syndrome. However, there is wide variability in phenotype among patients with mutations affecting type IV collagen that depends on a complex interplay of sex, genotype, and X-chromosome inactivation. This article reviews the genetic basis of collagen disorders of the kidney as well as potential treatments for these conditions, including direct alteration of the DNA, RNA therapies, and manipulation of collagen proteins.
Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Collagen Type IV; Gene Editing; Genetic Therapy; Humans; Molecular Chaperones; Nephritis, Hereditary; Protein Isoforms; RNA Interference; RNA, Small Interfering; mRNA Vaccines
PubMed: 33849932
DOI: 10.2215/CJN.19171220 -
Current Opinion in Nephrology and... May 2024With the latest classification, variants in three collagen IV genes, COL4A3 , COL4A4 , and COL4A5 , represent the most prevalent genetic kidney disease in humans,... (Review)
Review
PURPOSE OF REVIEW
With the latest classification, variants in three collagen IV genes, COL4A3 , COL4A4 , and COL4A5 , represent the most prevalent genetic kidney disease in humans, exhibiting diverse, complex, and inconsistent clinical manifestations. This review breaks down the disease spectrum and genotype-phenotype correlations of kidney diseases linked to genetic variants in these genes and distinguishes "classic" Alport syndrome (AS) from the less severe nonsyndromic genetically related nephropathies that we suggest be called "Alport kidney diseases".
RECENT FINDINGS
Several research studies have focused on the genotype-phenotype correlation under the latest classification scheme of AS. The historic diagnoses of "benign familial hematuria" and "thin basement membrane nephropathy" linked to heterozygous variants in COL4A3 or COL4A4 are suggested to be obsolete, but instead classified as autosomal AS by recent expert consensus due to a significant risk of disease progression.
SUMMARY
The concept of Alport kidney disease extends beyond classic AS. Patients carrying pathogenic variants in any one of the COL4A3/A4/A5 genes can have variable phenotypes ranging from completely normal/clinically unrecognizable, hematuria without or with proteinuria, or progression to chronic kidney disease and kidney failure, depending on sex, genotype, and interplays of other genetic as well as environmental factors.
Topics: Humans; Nephritis, Hereditary; Hematuria; Kidney; Collagen Type IV; Mutation
PubMed: 38477333
DOI: 10.1097/MNH.0000000000000983