Hiperostosis cortical congénita: una causa infrecuente de llanto inconsolable del lactante. Presentación de caso clínico / Congenital cortical hyperostosis: a rare cause of inconsolable crying in a baby. Clinical case report

Se presenta el caso de un lactante de 2 meses que fue llevado a consulta varias veces por llanto problemático, inicialmente interpretado como de causa gastrointestinal. Dado que el síntoma persistía, se sospechó de una fractura debido a su asociación con la movilización de los miembros y la palpación de una tumoración en la cara anterior de la tibia derecha. Las radiografías mostraron compromiso poliostótico diafisario y lesiones compatibles con compromiso cortical de huesos largos. Se realizó el diagnóstico operativo de síndrome de Caffey-De Toni-Silverman y se inició el tratamiento con antiinflamatorios no esteroideos, lo que resultó en una remisión sintomática. Posteriormente, se confirmó el diagnóstico mediante la identificación de la variante patogénica COL1A1 en estado heterocigota. Se trata de una patología rara de la cual se estima una incidencia de 48/100 000 y hay menos de 150 casos descritos al momento.

Here we describe the case of a 2-month-old infant who consulted several times due to excessive crying, initially interpreted as having a gastrointestinal cause. Since the symptom persisted, a fracture was suspected due to its association with mobilization of the limbs and palpation of a mass on the anterior aspect of the right tibia. X-rays showed diaphyseal polyostotic involvement and lesions compatible with cortical involvement of long bones. Caffey-De Toni-Silverman syndrome was diagnosed and treatment with nonsteroidal anti-inflammatory drugs was initiated, resulting in symptom remission. Subsequently, the diagnosis was confirmed by the identification of the pathogenic heterozygous variant COL1A1. This is a rare condition with an estimated incidence of 48/100 000 individuals, and less than 150 cases have been described to date.

Effect of ultrasound combined with 4-hydroxyphenyl-retinamide lipid microbubbles on type Ⅰ collagen α1 chain expression in keloid-derived fibroblasts / 中华皮肤科杂志

Objective:To investigate the effect of ultrasound combined with 4-hydroxyphenyl-retinamide (4-HPR) lipid microbubbles on type Ⅰ collagen α1 chain (COL1A1) protein expression in keloid-derived fibroblasts.Methods:In vitro cultured keloid-derived fibroblasts were divided into 3 groups: control group receiving conventional culture with incomplete Dulbecco′s modified Eagle′s medium (DMEM) , 4-HPR lipid microbubble group cultured with incomplete DMEM containing 15 mg/L 4-HPR lipid microbubbles, and ultrasound + 4-HPR lipid microbubble group cultured with incomplete DMEM containing 15 mg/L 4-HPR lipid microbubbles under ultrasound treatment. After 24-hour treatment, reverse transcription (RT) -PCR and Western blot analysis were performed to determine the mRNA and protein expression of COL1A1 in keloid-derived fibroblasts in each group. Intergroup comparison was carried out by using t test. Results:The mRNA relative expression level of COL1A1 was 1.00 ± 0.18, 0.69 ± 0.15 and 0.35 ± 0.18 in the control group, 4-HPR lipid microbubble group and ultrasound + 4-HPR lipid microbubble group respectively, and the protein relative expression level of COL1A1 was 0.93 ± 0.03, 0.74 ± 0.07 and 0.44 ± 0.06 in the above 3 groups respectively. Moreover, the mRNA and protein expression of COL1A1 was significantly lower in the 4-HPR lipid microbubble group and ultrasound + 4-HPR lipid microbubble group than in the control group ( P < 0.05 or 0.001) , and lower in the ultrasound + 4-HPR lipid microbubble group than in the 4-HPR lipid microbubble group ( P < 0.05) . Conclusion:Ultrasound combined with 4-HPR lipid microbubbles could markedly inhibit the mRNA and protein expression of COL1A1 in keloid-derived fibroblasts.

Fenugreek (Trigonella foenum-graceum) increases postmenopausal fibroblast-associated COL1A1 and COL3A1 production dominantly through its binding to estrogen receptor beta

In postmenopausal women, oral or topical administration of estradiol increases skin thickness and collagen synthesis,such as collagen type 1 alpha 1 (COL1A1) and collagen type 3 alpha 1 (COL3A1). Due to undesirable side effectsof estradiol, such as risks of breast and endometrium pathology, topical phytoestrogens are alternative treatments foraging-related skin changes. Phytoestrogen is a nonsteroidal substance derived from plants, like fenugreek (Trigonellafoenum-graceum L.), which has an estrogen like composition that appears to mimic estradiol. The mechanism ofaction remains unknown, especially in fibroblast-associated COL1A1 and COL3A1 production. In vitro experimentswere conducted using postmenopausal women's fibroblasts with estrogen receptor (ER) antagonists. Cell isolationused explant and enzymatic techniques with ELISA kit (MyBioSource, California) for COL1A1 and COL3A1. Pairedstudent t-tests compared results between control (no treatment), fenugreek extract 2 µg/ml alone, fenugreek extract 2µg/ml with receptor antagonists for ERα, ERβ, and both receptors. Greater suppresion of COL1A1 and COL3A1 wereshown by both antagonists ERα / ERβ group and antagonist ERβ group compared to antagonist ERα group. Theseresults indicate that the fenugreek increases secretion of COL1A1 and COL3A1 through ERα, ERβ, and is mainlymediated by ERβ in post menopausal women’s fibroblasts.

Co-occurrence of heterozygous mutations in COL1A1 and SERPINF1 in a high-risk pregnancy complicated by osteogenesis imperfecta

Mutations in several genes, including SERPRINF1 and COL1A1, have been associated with the development of osteogenesis imperfecta (OI). Here, we reported the co-occurrence of a rare heterozygous variant (c.167C>G p.Ala56Gly) in SERPRINF1 and a novel heterozygous mutation (c.1634G>A p.Gly545Asp) in COL1A1 in a foetus with a severe form of OI. Bioinformatics modelling revealed that the effect of the mutation on SPERINF1 is neutral. In contrast, the mutation in COL1A1 is deleterious. It is predicted to cause distortion of the α (1) chain of the type I collagen and results in structural instability of the protein. Therefore, a novel dominant variant of COL1A1 likely underlies the severe foetal pathology observed, although we do not exclude the possibility that the heterozygous mutations in SERPINF and COL1A1 may interact and co-ordinately cause pathogenesis. This novel COL1A1 mutation is recommended to be included in the diagnostic panels for OI.

The Effect of Trigonella foenum-graceum L. (Fenugreek) Towards Collagen Type I Alpha 1 (COL1A1) and Collagen Type III Alpha 1 (COL3A1) on Postmenopausal Woman's Fibroblast

Trigonella foenum-graceum L. (fenugreek) is a phytoestrogen, a nonsteroidal organic chemical compound from plants which has similar mechanism of action to sex hormone estradiol-17β. This study aims to assess the effectivity of fenugreek seeds extract on collagen type I alpha 1 (COL1A1) and collagen type III alpha 1 (COL3A1) which are both decreased in aging skin and become worsen after menopause. This in vitro experimental study used old human dermal fibroblast from leftover tissue of blepharoplasty on a postmenopausal woman (old HDF). As a control of the fenugreek's ability to trigger collagen production, we used fibroblast from preputium (young HDF). Subsequent to fibroblast isolation and culture, toxicity test was conducted on both old and young HDF by measuring cell viability on fenugreek extract with the concentration of 5 mg/mL to 1.2 µg/mL which will be tested on both HDF to examine COL1A1 and COL3A1 using ELISA, compared to no treatment and 5 nM estradiol. Old HDF showed a 4 times slower proliferation compared to young HDF (p<0.05). Toxicity test revealed fenugreek concentration of 0.5 – 2 µg/mL was non-toxic to both old and young HDF. The most significant fenugreek concentration to increase COL1A1 and COL3A1 secretion was 2 µg/mL (p<0.05).

Bioinformatics analysis of COL1A1 regulated by miR-129-5p as a potential therapeutic target for gastric cancer / 南方医科大学学报

OBJECTIVE@#To explore the pathogenesis of gastric cancer through a bioinformatic approach to provide evidence for the prevention and treatment of gastric cancer.@*METHODS@#The differentially expressed genes (DEGs) in gastric cancer and normal gastric mucosa in GSE79973 dataset were analyzed using GEO2R online tool. GO analysis and KEGG pathway enrichment analysis of the DEGs in DAVID database were performed. The protein interaction network was constructed using STRING database, and the key genes (Hub genes) were screened and their functional modules were analyzed using Cytoscape software. The GEPIA database was used to validate the Hub genes, and the Target Scan database was used to predict the microRNAs that regulate the target genes; OncomiR was used to analyze the expressions of the microRNAs in gastric cancer tissues and their relationship with the survival outcomes of the patients.@*RESULTS@#A total of 181 DEGs were identified in gastric cancer, and 10 hub genes were screened by the protein- protein interaction network. Functional analysis showed that these DEGs were involved mainly in protein digestion and absorption, PI3K-Akt signaling pathway, ECM-receptor interaction and platelet activation signal pathway. GEPIA database validation showed that COL1A1 was highly expressed in gastric cancer tissues and was associated with a poor prognosis of patients with gastric cancer. MiR-129-5p was found to bind to the 3'UTR of COL1A1 mRNA, and compared with that in normal tissues, miR-129-5p expression was obviously down-regulated in gastric cancer tissues, and was correlated with the prognosis of the patients.@*CONCLUSIONS@#COL1A1 under regulation by MiR-129-5p is a potential therapeutic target for gastric cancer.

LncRNA XIST promotes extracellular matrix synthesis, proliferation and migration by targeting miR-29b-3p/COL1A1 in human skin fibroblasts after thermal injury

Background: Long noncoding RNAs (lncRNAs) have been reported to be associated with dermis process during burn wound healing. This study aimed to investigate the role of lncRNA X-inactive specific transcript (XIST) in human skin fibroblasts (HSF) and extracellular matrix (ECM) as well as the regulatory network of XIST/microRNA-29b-3p (miR-29b-3p)/collagen 1 alpha 1 (COL1A1). Methods: The wound samples were collected from 25 patients with deep partial thickness burn at day 5 after burn. The thermal injured model was established using HSF cells. The expressions of XIST, miR-29b-3p and COL1A1 were measured by quantitative real-time polymerase chain reaction and western blot. ECM synthesis, cell proliferation and migration were detected by western blot, cell counting kit-8 and trans-well assays, respectively. The interaction between miR-29b-3p and XIST or COL1A1 was explored by bioinformatics analysis and luciferase reporter assay. Results: The expressions of XIST and COL1A1 were enhanced but miR-29b-3p expression was decreased after thermal injury. XIST overexpression promoted ECM synthesis, cell proliferation and migration in thermal injured HSF cells. However, XIST knockdown played an opposite effect. miR-29b-3p overexpression inhibited ECM synthesis, cell proliferation and migration, which was reversed by XIST. COL1A1 silence suppressed ECM synthesis, cell proliferation and migration by miR-29b-3p targeting. Moreover, COL1A1 up-regulation weakened the effect of XIST silence on ECM synthesis and HSF cell function. Conclusion: XIST promoted ECM synthesis, cell proliferation and migration by sponging miR-29b-3p and targeting COL1A1 in HSF cells after thermal injury, indicating the promoting role of XIST in wound healing.

Pedigree analysis of a osteogenesis imperfect and prolactinoma family caused by a newly found gene mutation in COL1A1 / 中华内分泌代谢杂志

Objective To explore the collagen, typeⅠ, α 1 chain ( COL1A1) gene mutation in a family with type 1 osteogenesis imperfect. Methods The medical records and DNA samples of an osteogenesis imperfect patient and her family members were collected, and their DNA sequencing were performed and compared with 50 non-relative healthy control from the same area. Results The proband and her three family members ( father, younger brother, and younger nephew) with clinical features of osteogenesis imperfect as well as prolactinoma were confirmed of COL1A1 gene mutation at the 24th intron with a shear mutation of c. 1669-1 G＞A which was not reported previously. Other family members were genetically normal compared with the normal. Conclusions We found a new COL1A1 gene mutation family and mutation site, but the relationship between osteogenesis imperfect and prolactinoma was unknown.

A novel de novo COL1A1 mutation in a Thai boy with osteogenesis imperfecta born to consanguineous parents

Abstract Osteogenesis imperfecta (OI) is genetically heterogeneous. Mutations in COL1A1 and COL1A2 are responsible for at least 90% of the cases, which are transmitted in an autosomal dominant manner or are de novo events. We identified a Thai boy with OI whose parents were first cousins. Because the proband was the product of a consanguineous marriage, we hypothesized that he might be homozygous for a mutation in a known gene causing a recessive form of OI. Using whole exome sequencing (WES), we did not find any pathogenic mutations in any known gene responsible for an autosomal recessive form of OI. Instead, we identified a COL1A1 frameshift mutation, c.1290delG (p.Gly431Valfs*110) in heterozygosis. By Sanger sequencing, the mutation was confirmed in the proband, and not detected in his parents, indicating that it was a de novo mutation. These findings had implication for genetic counseling. In conclusion, we expanded the mutational spectrum of COL1A1 and provided another example of a de novo pathogenic mutation in heterozygosis in a patient born to consanguineous parents.

Total flavonoids from arachniodes exilispromotes osteogenic differentiation of hUCMSCs / 中国药理学通报

Aim To study the role of the total flavonoids from arachniodes exilis(TFAE) in osteogenic differentiation of human umbilical cord mesenchymal stem cells(hUCMSCs).Methods hUCMSCs were isolated and cultured by tissue explants adherent method, hUCMSCs at passage 3 were used to do the experiment, hUCMSCs were treated by different concentrations of TFAE, and cellular viability was measured by CCK 8 assay;alkaline phosphatase(ALP) activity was tested by AMP method;calcium nodule formation was detected by alizarin red staining;expression level of osteogenesis-related gene type I collagen enzyme a1(collagen type Ia1, Col1a1), osteopontin(OPN), Runx2, Osterix(Osx) mRNA was measured by RT-PCR;expression level of Col1a1,OPN protein was measured by Western blot.Results Certain concentration of TFAE(1 mg·L-1, 5 mg·L-1) promoted cellular proliferation, calcium nodules were more, ALP activity was enhanced;expression level of osteogenesis-related gene Col1a1, OPN, Runx2, OsxmRNA and Col1a1, OPN protein was up-regulated.Conculsion A certain concentration of TFAE promotes proliferation and osteogenic differentiation of hUCMSCs.

miR-498 inhibits A549 cell migration and invasion by down-regulating FOXM1 / 西安交通大学学报(医学版)

Objective To verify whether miR-498 can inhibit A549 cell migration and invasion by down-regulating FOXM1.Methods miR-498 mimic and miR-NC were transfected into A549 cells.Wound healing and Transwell method were employed to test the migratory ability and invasion ability of A549 cells;Western blot was used to detect the expressions of COL1A1,COL1A5 and FOXM1 in A549 cells.Luciferase assay was used to confirm whether FOXM1 is the target gene of miR-498.Results Compared with those in the control group,the expressions of COL1A1,COL1A5 and FOXM1 were decreased,and the migration and invasion abilities of A549 cells were decreased in the miR-498 group (both P<0 .01 ).The luciferase activity of the FOXM1-3′-UTR plasmid was significantly suppressed by miR-498 (P<0 .05 );over-expression of FOXM1 could reverse the effect of miR-498 on A549 cells.Conclusion miR-498 inhibits A549 cell migration and invasion by down-regulating FOXM1.

MicroRNA-98 inhibits the cell proliferation of human hypertrophic scar fibroblasts via targeting Col1A1

BACKGROUND: Hypertrophic scarring (HS) is a severe disease, and results from unusual wound healing. Col1A1 could promote the hypertrophic scar formation, and the expression of Col1A1 in HS tissue was markedly higher than that in the normal. In present study, we aimed to identify miRNAs as post-transcriptional regulators of Col1A1 in HS. METHODS: MicroRNA-98 was selected as the key miRNA comprised in HS. The mRNA levels of miR-98 in HS tissues and the matched normal skin tissues were determined by qRT-PCR. MTT and flow cytometry were used to determine the influence of miR-98 on cell proliferation and apoptosis of HSFBs, respectively. Col1A1 was found to be the target gene of miR-98 using luciferase reporter assay. Luciferase assay was performed to determine the relative luciferase activity in mimic NC, miR-98 mimic, inhibitor NC and miR-98 inhibitor with Col1A13'-UTR wt or Col1A13'-UTR mt reporter plasmids. The protein expression of Col1A1 in HSFBs after transfection with mimic NC, miR-98 mimic, inhibitor NC and miR-98 inhibitor were determined by western blotting. RESULTS: The mRNA level of miR-98 in HS tissues was much lower than that in the control. Transfection of HSFBs with a miR-98 mimic reduced the cell viability of HSFBs and increased the apoptosis portion of HSFBs, while inhibition of miR-98 increased cell viability and decreased apoptosis portion of HSFBs. miR-98 inhibitor increased the relative luciferase activity significantly when cotransfected with the Col1A1-UTR reporter plasmid, while the mutant reporter plasmid abolished the miR-98 inhibitor-mediated increase in luciferase activity. Western blotting revealed that overex-pression of miR-98 decreased the expression of Col1A1. CONCLUSIONS: Overexpression of miR-98 repressed the proliferation of HSFBs by targeting Col1A1.

Effect of perivitelline fluid from horseshoe crab on the expression of COL1A1 in dental pulp stem cells

Perivitelline fluid, extracted from the fertilized eggs of horseshoe crabs, has been reported to play a vital role in supporting embryogenesis as well as cell proliferation. The present study aims to evaluate the effect of PVF on the expression of COL1A1 in human dental pulp stem cells (DPSCs). The cells were grouped into two; untreated (control) and treated with a single dose of PVF (0.019 mg/ml). Gene expression was quantified for COL1A1 on day 1, 3 and 7 using reverse transcriptase PCR. The expression of COL1A1 on day 3 of treated group with PVF was the highest though there was a decline of COL1A1 expression on day 7. Mann Whitney test was utilized to determine the significance of COL1A1 expression between treated and untreated groups. Significant difference in the expression of COL1A1 was observed between the treated and untreated groups on day 3 though there was no significance in the expression on day 7. The present study indicates that PVF may have the potential to increase cell proliferation in human DPSCs.

Clinical study of molecular markers and COL1A1/PDGFB fusion gene in dermatofibrosarcoma protuberans / 中国肿瘤临床

Objective:To investigate the values of immunophenotype and the Collagen type1 alpha1/Proto-oncogene Proteins c-sis (COL1A1/PDGFB) fusion gene in the diagnosis of dermatofibrosarcoma protuberans (DFSP). Methods:IHC markers and the COL1A1/PDGFB fusion gene were detected by IHC staining and interphase fluorescence in situ hybridization (FISH) in 73 cases previously diagnosed as DFSP. A total of 85 and 10 non-DFSP cases were also included as controls for IHC staining and FISH, respectively. Results:In the 73 DFSP cases, the positive detection rates for immunohistochemical marker vimentin, CD34, CD99, S100, desmin and SMA were 100%, 91.78%, 61.64%, 0, 0, and 6.85%, correspondingly. Protein expression levels in these cases varied from the control group, and CD34 ex-pression was significantly different among the differential diagnoses. The positive detection rate for the COL1A1/PDGFB fusion gene was 86.96%(60/69), whereas the gene expression in the control group was negative. Conclusion:The COL1A1/PDGFB fusion gene is a highly specific and sensitive marker in the diagnosis of DFSP. CD34 is a suitable marker for DFSP.

PCR-HRM Analysis for Gene Mutation Screening in a Child with Osteogenesis Imperfecta / 天津医药

Objective To investigate COL1A1 gene mutation by PCR-high resolution melting (PCR-HRM) and an-alyze the correlation between genotype and clinical phenotype in a child (proband) with osteogenesis imperfecta (OI). Methods The family history of OI pedigree along with the clinical data was collected. Blood samples from the proband and his family members, as well as 50 normal controls, were collected. The mutation of COL1A1 gene was screened using PCR-HRM and validated by the gene sequence. Results The detection of PCR-HRM showed the abnormal result of COL1A1 17 exon in proband with a lower melting temperature (Tm) value than that of normal controls by 0.4℃. There were signifi-cant differences in the standardization melting curve and the different melting curve between the proband and the normal controls. The sequencing result was c.1138G>A, which meant that cDNA of 1138 base G mutation into A. The mutations transformed the amino acid glycine into a serine at amino acid 380(P. Gly 380 Ser), which resulted in missense mutations. The proband’s father and grandmother had the same mutation of COL1A1 gene. The mutation was not found in the proband’s mother and normal controls. There was no report for such mutation in Chinese population. Pedigree analysis showed the fami-ly genetic characteristics of autosomal dominant inheritance. The proband was clinically diagnosed as OI type Ⅳwith more severe clinical phenotype. Conclusion PCR-HRM analysis is a new effective method for genetic screening of OI. COL1A1 mutation of c.1138G>A is a newly discovered mutation in Chinese population. Gly replaced inαhelical domain may lead to a more severe clinical phenotype.

Reversible prostaglandin-induced cortical hyperostosis in an infant without 3040C→T mutation in COL1A1

Background: A hereditary form of infantile cortical hyperostosis (ICH), known as Caffey disease, was recently found to be caused by a heterozygous 3040C → T mutation in the COL1A1 gene. Objective: To determine whether a similar mutation was also responsible for a sporadic case of ICH. Methods: We identified a Thai male infant who was a sporadic case of ICH. He had symmetric cortical hyperostosis of all of his long bones, clavicles, and ribs occurring after a prolonged infusion of prostaglandin E1 (PGE1) for a cyanotic congenital heart disease. Mutation analysis of COL1A1 was performed in the patient and his parents by restriction enzyme digestion of PCR products. Results: The particular mutation was not found in our case and in his parents. A follow-up after 15 months demonstrated that the child had normal growth and development. Repeated imaging studies revealed markedly decreased cortical thickenings of the affected bones. Conclusion: Our findings confirm that PGE1-induced cortical hyperostosis is reversible and does not associate with the COL1A1 3040C→T mutation. Keywords: COL1A1, infantile cortical hyperostosis, prostaglandin, reversible.

Detection of Gene Mutation and Relationship between Phenotype and Genotype in Four Chinese Families with Osteogenesis Imperfecta / 实用儿科临床杂志

T mutation was detected in the 4th propositus at the 9th intron,but any COL1A1 or COL1A2 gene mutation was detected in the third propositus and the other members in the former families.Conclusions The genetic mutation of COL1A1 may result in OI in China,but other mutations may also exist.Moreover,the phenotype was influenced not only by OI genotype,but also by the genetic background,environment and other factors.