Mutations In Collagen Type Research Articles

Evaluating neural crest cell migration in a Col4a1 mutant mouse model of ocular anterior segment dysgenesis

The periocular mesenchyme (POM) is a transient migratory embryonic tissue derived from neural crest cells (NCCs) and paraxial mesoderm that gives rise to most of the structures in front of the eye. Morphogenetic defects of these structures can impair aqueous humor outflow, leading to elevated intraocular pressure and glaucoma. Mutations in collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) cause Gould syndrome – a multisystem disorder often characterized by variable cerebrovascular, ocular, renal, and neuromuscular manifestations. Approximately one-third of individuals with COL4A1 and COL4A2 mutations have ocular anterior segment dysgenesis (ASD), including congenital glaucoma resulting from abnormalities of POM-derived structures. POM differentiation has been a major focus of ASD research, but the underlying cellular mechanisms are still unclear. Moreover, earlier events including NCC migration and survival defects have been implicated in ASD; however, their roles are not as well understood. Vascular defects are among the most common consequences of COL4A1 and COL4A2 mutations and can influence NCC survival and migration. We therefore hypothesized that NCC migration might be impaired by COL4A1 and COL4A2 mutations. In this study, we used 3D confocal microscopy, gross morphology, and quantitative analyses to test NCC migration in Col4a1 mutant mice. We show that homozygous Col4a1 mutant embryos have severe embryonic growth retardation and lethality, and we identified a potential maternal effect on embryo development. Cerebrovascular defects in heterozygous Col4a1 mutant embryos were present as early as E9.0, showing abnormal cerebral vasculature plexus remodeling compared to controls. We detected abnormal NCC migration within the diencephalic stream and the POM in heterozygous Col4a1 mutants whereby mutant NCCs formed smaller diencephalic migratory streams and POMs. In these settings, migratory NCCs within the diencephalic stream and POM localize farther away from the developing vasculature. Our results show for the first time that Col4a1 mutations lead to cranial NCCs migratory defects in the context of early onset defective angiogenesis without affecting cell numbers, possibly impacting the relation between NCCs and the blood vessels during ASD development.

Cranio-cervical abnormalities in moderate-to-severe osteogenesis imperfecta - Genotypic and phenotypic determinants.

Cranio-cervical anomalies are significant complications of osteogenesis imperfecta (OI), a rare bone fragility disorder that is usually caused by mutations in collagen type I encoding genes. To assess cranio-cervical anomalies and associated clinical findings in patients with moderate-to-severe OI using 3D cone beam computed tomography (CBCT) scans. Cross-sectional analysis of CBCT scans in 52 individuals with OI (age 10-37 years; 32 females) and 40 healthy controls (age 10-32 years; 26 females). Individuals with a diagnosis of OI type III (severe, n = 11), type IV (moderate, n = 33) and non-collagen OI (n = 8) were recruited through the Brittle Bone Disorders Consortium. Controls were recruited through the orthodontic clinic of the University of Missouri-Kansas City (UMKC). OI and control groups were similar in mean age (OI: 18.4 [SD: 7.2] years, controls: 18.1 [SD: 6.3] years). The cranial base angle was increased in the OI group (OI: mean 148.6° [SD: 19.3], controls: mean 130.4° [SD: 5.7], P = .001), indicating a flatter cranial base. Protrusion of the odontoid process into the foramen magnum (n = 7, 14%) and abnormally located odontoid process (n = 19, 37%) were observed in the OI group but not in controls. Low stature, expressed as height z-score (P = .01), presence of DI (P = .04) and being male (P = .04) were strong predictors of platybasia, whereas height z-score (P = .049) alone was found as positive predictor for basilar impression as per the Chamberlain measurement. The severity of the phenotype in OI, as expressed by the height z-score, correlates with the severity of cranial base anomalies such as platybasia and basilar impression in moderate-to-severe OI. Screening for cranial base anomalies is advisable in individuals with moderate-to-severe OI, with special regards to the individuals with a shorter stature and DI.

A novel compound heterozygous mutation of COL6A3 in Chinese patients with isolated cervical dystonia.

The etiology and pathogenesis of idiopathic dystonia remain obscure. Recent studies revealed that compound heterozygous mutations in collagen type VI alpha-3 gene COL6A3 may cause recessive isolated dystonia (DYT)-27. However, whether COL6A3 mutations are associated with Chinese patients with isolated dystonia is not yet reported. In this study, 45 Chinese patients with isolated cervical dystonia were recruited, and their blood DNA samples were subjected to whole-exome sequencing. The potential causal variants of COL6A3 were identified based on the criteria of the American College of Medical Genetics and Genomics and by prediction software. Among 45 isolated cervical dystonia patients, 18 patients (10 female patients and eight male patients) were found to have seven potential causal variants in the COL6A3 gene. Among these variants, a compound heterozygous mutation was found in one patient. One allele had a c.1264G>A mutation in exon 4 that resulted in an amino acid substitution of methionine for valine at codon 422 (p.Val422Met) and the other a c.8965+9G>A mutation involving a splicing change in exon 40. In addition, other five missense variants, including c.958G>A (p.Ala320Thr), c.1478T>C (p.Val493Ala), c.1597C>T (p.Arg533Cys), c.1762G>A (p.Asp588Asn), and c.4912G>A (p.Ala1638Thr), were identified as well. We identified a novel deleterious compound heterozygous mutation as well as five missense variants in the COL6A3 gene of Chinese patients with cervical dystonia. These findings may expand the spectrum of the COL6A3 genotype in isolated dystonia.

Next-Generation Sequencing (NGS) Analysis Illustrates the Phenotypic Variability of Collagen Type IV Nephropathies

Mutations in COL4A3-A5 cause a spectrum of glomerular disorders, including thin basement membrane nephropathy (TBMN) and Alport syndrome (AS). The wide application of next-generation sequencing (NGS) in the last few years has revealed that mutations in these genes are not limited to these clinical entities. In this study, 176 individuals with a clinical diagnosis of inherited kidney disorders underwent an NGS-based analysis to address the underlying cause; those who changed or perfected the clinical diagnosis after molecular analysis were selected. In 5 out of 83 individuals reaching a molecular diagnosis, the genetic result was unexpected: three individuals showed mutations in collagen type IV genes. These patients showed the following clinical pictures: (1) familial focal segmental glomerulosclerosis; (2) end-stage renal disease (ESRD) diagnosed incidentally in a 49-year-old man, with diffuse cortical calcifications on renal imaging; and (3) dysmorphic and asymmetric kidneys with multiple cysts and signs of tubule-interstitial defects. Genetic analysis revealed rare heterozygote/compound heterozygote COL4A4-A5 variants. Our study highlights the key role of NGS in the diagnosis of inherited renal disorders and shows the phenotype variability in patients carrying mutations in collagen type IV genes.

The potential of miR-153 as aggressive prostate cancer biomarker.

Prostate cancer (PC) is one of the most frequently diagnosed cancers in males. MiR-153, as a member of the microRNA (miRNA) family, plays an important role in PC. This study aims to explore the expression and possible molecular mechanisms of the miR-153 action. Formalin-fixed paraffin-embedded (FFPE) tissues were collected from prostatectomy specimens of 29 metastatic and 32 initial stage PC patients. Expression levels of miR-153 were measured using real-time reverse transcription polymerase chain reaction (qRT-PCR). 2-ΔΔCT method was used for quantitative gene expression assessment. The candidate target genes for miR-153 were predicted by TargetScan. Mutations in target genes of miR-153 were identified using exome sequencing. Protein-protein interaction (PPI) networks, Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to investigate the potential molecular mechanisms of miR-153 in PC. MiR-153 was significantly up-regulated in PC tissues compared to non-cancerous tissues. The analysis of correlation between the expression level of miR-153 and clinicopathological factors revealed a statistically significant correlation with the stage of the tumor process according to tumor, node, metastasis (TNM) staging system (p=0.0256). ROC curve analysis was used to evaluate the predictive ability of miR-153 for metastasis development and it revealed miR-153 as a potential prognostic marker (AUC=0.85; 95%CI 0.75-0.95; sensitivity=0.72, specificity=0.86)). According to logistic regression model the high expression of miR-153 increased the risk of metastasis development (odds ratios=3.14, 95% CI 1.62-8.49; p-value=0.006). Whole exome sequencing revealed nonsynonymous somatic mutations in collagen type IV alpha 1 (COL4A1), collagen type IV alpha 3 (COL4A3), forkhead box protein O1 (FOXO1), 2-hydroxyacyl-CoA lyase 1 (HACL1), hypoxia-inducible factor 1-alpha (HIF-1A), and nidogen 2 (NID2) genes. Moreover, KEGG analysis revealed that the extracellular matrix-receptor (ECM-receptor) interaction pathway is mainly involved in PC. MiR-153 is up-regulated in PC tissues and may play an important role in aggressive PC by targeting potential target genes.

Tendon properties in a mouse model of severe osteogenesis imperfecta

ABSTRACT Purpose/Aim of the study Osteogenesis imperfecta is a heritable bone disorder that is usually caused by mutations in collagen type I encoding genes. The impact of such mutations on tendons, a structure with high collagen type I content, remains largely unexplored. We hypothesized that tendon properties are abnormal in the context of a mutation affecting collagen type I. The main purpose of the study was to assess the anatomical, mechanical, and material tendon properties of Col1a1 Jrt/+ mice, a model of severe dominant OI. Materials and Methods The Flexor Digitorum Longus (FDL) tendon of Col1a1 Jrt/+ mice and wild-type littermates (WT) was assessed with in vitro mechanical testing. Results The results showed that width and thickness of FDL tendons were about 40% larger in WT (p < 0.01) than in Col1a1 Jrt/+ mice, whereas the cross-sectional area was 138% larger (p < 0.001). The stiffness, peak- and yield-force were between 160% and 194% higher in WT vs. Col1a1 Jrt/+ mice. The material properties did not show significant differences between mouse strains with differences <15% between WT and Col1a1 Jrt/+ (p > 0.05). Analysis of the Achilles tendon collagen showed no difference between mice strains for the content but collagen solubility in acetic acid was 66% higher in WT than in Col1a1 Jrt/+ (p < 0.001). Conclusions This study shows that the FDL tendon of Col1a1 Jrt/+ mice has reduced mechanical properties but apparently normal material properties. It remains unclear whether the tendon phenotype of Col1a1 Jrt/+ mice is secondary to muscle weakness or a direct effect of the Col1a1 mutation or a combination of both.

Elevated TGFβ signaling contributes to cerebral small vessel disease in mouse models of Gould syndrome

Cerebral small vessel disease (CSVD) is a leading cause of stroke and vascular cognitive impairment and dementia. Studying monogenic CSVD can reveal pathways that are dysregulated in common sporadic forms of the disease and may represent therapeutic targets. Mutations in collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) cause highly penetrant CSVD as part of a multisystem disorder referred to as Gould syndrome. COL4A1 and COL4A2 form heterotrimers [a1α1α2(IV)] that are fundamental constituents of basement membranes. However, their functions are poorly understood and the mechanism(s) by which COL4A1 and COL4A2 mutations cause CSVD are unknown. We used histological, molecular, genetic, pharmacological, and in vivo imaging approaches to characterize central nervous system (CNS) vascular pathologies in Col4a1 mutant mouse models of monogenic CSVD to provide insight into underlying pathogenic mechanisms. We describe developmental CNS angiogenesis abnormalities characterized by impaired retinal vascular outgrowth and patterning, increased numbers of mural cells with abnormal morphologies, altered contractile protein expression in vascular smooth muscle cells (VSMCs) and age-related loss of arteriolar VSMCs in Col4a1 mutant mice. Importantly, we identified elevated TGFβ signaling as a pathogenic consequence of Col4a1 mutations and show that genetically suppressing TGFβ signaling ameliorated CNS vascular pathologies, including partial rescue of retinal vascular patterning defects, prevention of VSMC loss, and significant reduction of intracerebral hemorrhages in Col4a1 mutant mice aged up to 8 months. This study identifies a novel biological role for collagen α1α1α2(IV) as a regulator of TGFβ signaling and demonstrates that elevated TGFβ signaling contributes to CNS vascular pathologies caused by Col4a1 mutations. Our findings suggest that pharmacologically suppressing TGFβ signaling could reduce the severity of CSVD, and potentially other manifestations associated with Gould syndrome and have important translational implications that could extend to idiopathic forms of CSVD.

N-Ethyl-N-Nitrosourea (ENU) induced Osteoporosis in Rats by inducing mutation in Collagen Type 1 protein–A Novel Method Development

Osteoporosis is a life-threatening condition that primarily affects women. Mice, rats, dogs, and rabbits have all been used as research animals. Bone strength, bone micro architectural characteristics, and osteoporosis risk are all affected by genetic factors. In this sequence, Type I collagen is the primary bone protein encoded by the COLIA1 and COLIA2 genes. The goal of the study is to develop new model for osteoporosis in rats by using N-Ethyl-N- Nitrosourea (ENU) which particularly targets COL1A1. Further, we treated the osteoporotic rats with Collagen type protein, in order to cross check the disease induction. And Rats induced with ENU, exhibited mutation in COL1A1 gene increased in the levels of both serum and urine biochemical parameters like calcium, phosphorus, ALP and creatinine. PCR analysis reported the mutation in COL1A1 gene. The use of animal models of osteoporosis is required to better understand the complex nature of this condition and to create new preventive and treatment approaches.

Late Onset Junctional Epidermolysis Bullosa in Adulthood

Junctional Epidermolysis Bullosa of late onset (JEB-lo) is caused by mutations in collagen type XVII gene (COL17A1). Family and personal history, clinical presentation, exam findings, biopsy, and immunofluorescence testing were recorded and analyzed for the patient in our study. Based on the patient’s history of recurrent tense blisters on his lower extremities, recent skin exams, histologic findings on his biopsy and negative DIF studies as well as immunomapping, the clinical manifestations of the patient are most likely attributed to a late-onset variant of JEB due to a mutation in COL17A1. We conclude that recurrent tense blisters on the lower extremities, hyperhidrosis, nail dystrophy, and tooth enamel abnormalities can all result from JEB-lo. This study is important for adding to the range of clinical presentations of JEB-lo and raising clinician awareness.

Osteogenesis imperfecta and bisphosphonate

Osteogenesis Imperfecta (OI) is defined as genetic disorders presented by various clinical presentations, such as bone deformities, abnormalities in dental structure, deafness, blue sclera, growth retardation, and ligament laxity. Most OI patients have a mutation in collagen type I alpha chains genes, COL1A1 and COL1A2. All those genes are expressed in osteoblasts and mostly responsible for the direct metabolism of collagen type I. Bisphosphonates (BPs), as potent antiresorptive agents, inhibit bone resorption through direct actions in the osteoclasts. They cut the excessive turnover rate and prevent bone tissue loss. The selection of BP regimens for OI patients is still a significant obstacle due to the lack of standardization of therapy and the lack of published evidence to determine the most appropriate type for different OI patients. The current use of BP and its benefit in OI are discussed in this review.

Compression Fractures and Partial Phenotype Rescue With a Low Phosphorus Diet in the Chihuahua Zebrafish Osteogenesis Imperfecta Model.

Osteogenesis imperfecta (OI) is a group of heritable disorders affecting bone and other connective tissues. Dominant OI forms are mainly caused by mutations in collagen type I. Patients suffer from skeletal deformities, fractures of long bones and vertebral compression fractures from early childhood onward. Altered collagen structure and excess mineralisation are the main causes for the bone phenotype. The Chihuahua (Chi/+) zebrafish has become an important model for OI. Given that reduced dietary phosphorus (P) intake reduces the bone mineral content and promotes bone matrix formation in teleosts, including zebrafish, we tested whether a low dietary P (LP) intake mitigates the OI phenotype in the Chi/+ model. To answer this question, we characterised the Chi/+ vertebral column phenotype at a morphological, cellular and subcellular level. We present the first description of vertebral compression fractures in Chi/+ and assess the effects of LP diet on the Chi/+ phenotype (Chi/+LP). Compared to untreated Chi/+, two months of LP dietary treatment decreases vertebral deformities in the abdominal region and reduces shape variation of caudal vertebral bodies to a condition more similar to wild type (WT). At the histological level, the osteoid layer, covering the bone at the vertebral body endplates in WT zebrafish, is absent in Chi/+, but it is partially restored with the LP diet. Whole mount-stained specimens and histological sections show various stages of vertebral compression fractures in Chi/+ and Chi/+LP animals. Both Chi/+ and Chi/+LP show abundant osteoclast activity compared to WT. Finally, the ultrastructure analysis of WT, Chi/+ and Chi/+LP shows Chi/+ and Chi/+LP osteoblasts with enlarged endoplasmic reticulum cisternae and a high protein content, consistent with intracellular retention of mutated collagen. Nevertheless, the secreted collagen in Chi/+LP appears better organised concerning fibre periodicity compared to Chi/+. Our findings suggest that a reduced mineral content of Chi/+ bone could explain the lower frequency of vertebral column deformities and the restored shape of the vertebral bodies in Chi/+LP animals. This, together with the improved quality of the bone extracellular matrix, suggests that two months of reduced dietary P intake can alleviate the severe bone phenotype in Chi/+ zebrafish.

Dentinogenesis Imperfecta and Caries in Osteogenesis Imperfecta among Vietnamese Children.

Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility and low bone mass, caused mainly by mutations in collagen type I encoding genes. The current study aimed to evaluate dentinogenesis imperfecta (DI), oral manifestations and caries status of OI children. Sixty-eight children (41 males, 27 females) aged from 3 to 17 years old (mean 9 ± 4.13) participated in the study. Participants were classified into three OI type groups (I—2 cases, III—31 cases and IV—35 cases). Clinical examination and an orthopantomogram were used to obtain prevalences and associations of DI, caries status, malocclusion, crossbite, open bite, eruption, impaction and missing teeth with OI. The prevalence of DI among OI patients was 47.1%, more common in OI type III than type IV. The yellow-brown discoloration type was more vulnerable to attrition than the opalescent-grey one in the primary dentition. OI seemed not to have a high risk of caries; the prevalence of caries was 69.1%. A high incidence of malocclusion, crossbite and open bite was observed. In-depth oral information would provide valuable data for better dental management in OI patients. Parents and general doctors should pay more attention to dental care to prevent caries and premature tooth loss.

Muscle transcriptome in mouse models of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder that is most often caused by mutations in collagen type I encoding genes. Even though bone fragility is the most conspicuous finding in OI, the muscle system is also affected. In the present study we explored the muscle phenotype related to collagen type I mutations on the transcriptome level. RNA sequencing was performed in gastrocnemius muscles of homozygous oim mice and of heterozygous Jrt mice, two models of severe OI. We found that oim and Jrt mice shared 27 differentially expressed genes, of which 11 were concordantly upregulated and 15 concordantly downregulated. Gene Set Enrichment Analysis revealed that in both oim and Jrt mice, genes involved in 'metabolism of lipids' were significantly enriched among upregulated genes. In addition, several genes coding for extracellular matrix components were upregulated in both oim and Jrt mice. Among downregulated genes, genes involved in 'muscle contraction' were enriched in both OI mouse models. These 'muscle contraction' genes coded for slow-twitch type I muscle fiber components. Another shared downregulated gene was Mss51, a metabolic stress-inducible factor that is found in mitochondria. These data show that two mouse models of severe OI share abnormalities in the expression of genes that code for extracellular matrix proteins, lipid and energy metabolism and structural proteins of type I muscle fibers. The muscle disturbances resulting from the collagen type I mutations in these mouse models could be viewed as a mild form of muscle dystrophy.

Generation of human induced pluripotent stem cell line (WMUi001-A) from a patient with aortic dissection.

A human induced pluripotent stem cell (hiPSC) line (WMUi001-A) was generated from the aortic tissue of a 47-year-old donor with aortic dissection and normal blood pressure. Integration-free episomal vector-mediated reprogramming was used for the generation of this iPSC line. The established iPSC line was found to express pluripotency markers, exhibit a differentiation potential in vitro, as well as display a normal karyotype. We further identified that this iPSC line contained a mutation in collagen type IV (COL4A2, R131M), which may serve as a useful tool for the disease modeling of aortic dissection.

Corneal recurrent erosions dystrophy in citizens and migrants in Finland

AbstractThe epithelial recurrent erosion dystrophy (ERED) is a rare autosomal dominant corneal disease. Recently, mutations in collagen type XVII, alpha 1 (COL17A1) gene were identified as the cause of ERED. We have identified four Finnish families and one Armenian family with recurrent erosions and a dominant inheritance pattern. Affected patients reported recurrent corneal erosions beginning at the age of 4–12 years. The frequency of erosions decreased in adult age. Corneal scarring and anterior stromal opacities with varying degree were observed. The visual acuity of some patients slowly deteriorated. Next‐generation exome sequencing was performed in seven affected individuals from the five families focusing on the large COL17A1 gene. Sequencing analysis revealed that all seven patients carried a known synonymous splice‐altering variant c.3156C&gt;T. Furthermore, five more family members were studied with Sanger sequencing. All twelve patients carried the same c.3156C&gt;T variant. The variant was not present in gnomAD database including of 12,562 Finns. A genealogical analysis revealed that in one Finnish family the variant originated from Sweden. The variant c.3156C&gt;T in COL17A1 is reported previously in English, American, Thai, New Zealand, and Tasmanian families with ERED. Our finding of the same variant in yet two other populations strengthens the evidence that this variant is the most frequent cause of ERED. The c.3156C&gt;T codon seems to be a hot spot for recurrent mutations.

Recurrent corneal erosions dystrophy (ERED) in a Finnish family is caused by a COL17A1 splice‐altering mutation

PurposeThe epithelial recurrent erosion dystrophy (ERED) is a rare autosomal dominant corneal disease. Recently, mutations in collagen type XVII, alpha 1 (COL17A1) gene have been identified as the cause of ERED. Here we report a Finnish family with recurrent erosions with dominant inheritance pattern. We performed COL17A1 candidate gene sequencing.MethodsFive affected and five unaffected family members underwent standard ophthalmological examination, corneal topography, anterior segment optical coherence tomography and in vivo confocal microscopy. Next‐generation exome sequencing of peripheral blood was made in two of the affected individuals to identify mutations in the large COL17A1 gene. Sanger sequencing was used to verify the presence of the identified variant in the other family members.ResultsAffected patients reported recurrent corneal erosions beginning at the age of 4‐6 years. The frequency of erosions decreased in adult age. Corneal scarring and anterior stromal opacities were observed. The visual acuity slowly deteriorated. Exome‐sequencing revealed a synonymous splice‐altering variant c.3156C&gt;T in COL17A1 in two affected patients. Sanger sequencing confirmed the presence of the same variant in four affected family members and its absence from two unaffected ones. The variant was not present in the Sequencing Initiative Suomi (SISu) database consisting of 10,490 Finns.ConclusionsThe variant c.3156C&gt;T in COL17A1 is reported recently in five English, American, New Zealand, and Tasmanian families with ERED. Our finding of the same synonymous variant in yet another population strengthens the evidence this variant is a frequent cause of ERED.

Health-Related Quality of Life in Adults with Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a systemic connective tissue disorder most often caused by mutations in collagen type 1 related genes. Patients with OI suffer from multiple fractures and various degrees of growth deficiency and bone deformity. It is unknown whether the systemic effect of defect collagen type 1 influences the quality of life in patients with OI. We therefore aimed to investigate health-related quality of life (HRQoL) in a well-characterized cohort of adult patients with OI. We included 85 adult patients with mild to severe OI (types I, III, and IV) and obtained information about skeletal- and non-skeletal phenotypes and patient demographics. We investigated physical and mental HRQoL using a validated questionnaire, SF-36, and compared the data to values obtained in a population without OI. Patients with mild, moderate, and severe OI all had lower mean scores on domains describing physical HRQoL and a lower mean physical component score compared to the general population, p<0.001. Patients with severe OI had lower mean scores on physical HRQoL, p<0.05. The scores on domains reflecting mental HRQoL were more inhomogenously affected, but did not differ significantly from the general population. OI has an impact on physical and some aspects of mental HRQoL. The scores on physical health were correlated to severity of the OI disease. The mental component score in the OI patients was unaffected and comparable with the general population.

Corrigendum] Clinical characteristics and the identification of novel mutations of COL1A1 and COL1A2 in 61Chinese patients with osteogenesis imperfecta.

Following the publication of this article, an interested reader drew to our attention that, in TableIV, we describe a c.1081C>T, p.Arg361X mutation in collagen typeI, alpha2 (COL1A2). Codon361 is a glycine residue, not an arginine, according to the transcript, Z74616.1. We re‑examined the original data, and identified that the mutation c.1081C>T, p.Arg361X was of the collagen typeI, alpha1 COL1A1 gene, and furthermore, it was not novel in the mutation spectrum of COL1A1. Therefore, in the paper, the c.1081C>T, p.Arg361X mutation should have appeared in TableIII (not TableIV), which described the clinical and genetic characteristics of probands with mutations in COL1A1, with an indication in the final column of the Table that it was not novel in the mutation spectrum of COL1A1. This error did not affect the major conclusions drawn in this study. We sincerely apologize for this mistake, and thank the reader of our article who drew this matter to our attention. [the original article was published in the Molecular Medicine Reports 14: 4918‑4926, 2016; DOI: 10.3892/mmr.2016.5835].

Clinical characteristics and the identification of novel mutations of COL1A1 and COL1A2 in 61Chinese patients with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is an inherited connective tissue disorder characterized by brittle bone fractures. The aim of the present study was to investigate the pathogenic gene mutation spectrum and clinical manifestations of mutations in collagen type I, alpha 1 (COL1A1) and collagen typeI, alpha2 (COL1A2) genes in Chinese patients with OI. A total of 61unrelated Chinese OI patients with COL1A1 and COL1A2 mutations were recruited. All the exons and the exon-intron boundaries of the COL1A1 and COL1A2 genes were amplified and directly sequenced and lumbar spine bone mineral density was measured by dual‑energy X‑ray absorptiometry. The mutations of the 61probands included 33missense mutations, 8nonsense mutations, 7splicing variants and 13frameshift mutations in COL1A1 and COL1A2 genes. A total of 25novel mutations were identified, including 18 in COL1A1 and 7in COL1A2. The mutations p.Gly257Arg, p.Gly767Ser and p.Gly821Ser in COL1A1 and p.Gly337Ser in COL1A2 may be located at a mutation hotspot for human OI due to the high repetition rate in OI patients. Family history was positive for OI in 33probands (54%). All probands had suffered fractures and the most common fracture site was the femur. A total of 49probands presented with blue sclerae (80.3%), 20probands suffered from dentinogenesis imperfecta (32.8%) and 1patient had hearing loss (1.6%). These findings may improve understanding of the pathogenic gene mutation spectrum and the clinical manifestations of mutations of COL1A1 and COL1A2 genes in Chinese patients with OI.

Albumin: innocent bystander or culprit?

alport syndrome (AS) is a hereditary glomerulopathy associated with hearing loss and ocular abnormalities that, if left untreated, inevitably progresses to glomerulosclerosis and end-stage renal disease (ESRD) ([6][1]). AS is caused by mutations in collagen type IV genes and is associated with