BACKGROUND We report a rare case of primary clinical presentation featuring elevated creatine kinase(CK)levels in a neonate,which is associated with the LAMA2 gene.In this case,a heterozygous mutation in exon5 of the ...BACKGROUND We report a rare case of primary clinical presentation featuring elevated creatine kinase(CK)levels in a neonate,which is associated with the LAMA2 gene.In this case,a heterozygous mutation in exon5 of the LAMA2 gene,c.715C>G(resulting in a change of nucleotide number 715 in the coding region from cytosine to gua-nine),induced an amino acid alteration p.R239G(No.239)in the patient,repre-senting a missense mutation.This observation may be elucidated by the neonatal creatine monitoring mechanism,a phenomenon not previously reported.CASE SUMMARY We analysed the case of a neonate presenting solely with elevated CK levels who was eventually discharged after supportive treatment.The chief complaint was identification of increased CK levels for 15 d and higher CK values for 1 d.Ad-mission occurred at 18 d of age,and despite prolonged treatment with creatine and vitamin C,the elevated CK levels showed limited improvement.Whole exo-me sequencing revealed the presence of a c.715C>G mutation in LAMA2 in the newborn,correlating with a clinical phenotype.However,the available informa-tion offers insufficient evidence for clinical pathogenicity.CONCLUSION Mutations in LAMA2 are associated with the clinical phenotype of increased neonatal CK levels,for which no specific treatment exists.Whole genome sequen-cing facilitates early diagnosis.展开更多
LAMA2-related congenital muscular dystrophy(LAMA2-CMD),characterized by laminin-α2 deficiency,is debilitating and ultimately fatal.To date,no effective therapy has been clinically available.Laminin-a1,which shares si...LAMA2-related congenital muscular dystrophy(LAMA2-CMD),characterized by laminin-α2 deficiency,is debilitating and ultimately fatal.To date,no effective therapy has been clinically available.Laminin-a1,which shares significant similarities with laminin-a2,has been proven as a viable compensatory modifier.To evaluate its clinical applicability,we establish a Lama2 exon-3-deletion mouse model(dy^(H)/dy^(H)).The dy^(H)/dy^(H) mice exhibit early lethality and typical LAMA2-CMD phenotypes,allowing the evaluation of various endpoints.In dy^(H)/dy^(H) mice treated with synergistic activation mediator-based CRISPRa-mediated Lama1 upregulation,a nearly doubled median survival is observed,as well as improvements in weight and grip.Significant therapeutical effects are revealed by MRl,serum biochemical indices,and muscle pathology studies.Treating LAMA2-CMD with LAMA1 upregulation is feasible,and early intervention can alleviate symptoms and extend lifespan.Additionally,we reveal the limitations of LAMA1 upregulation,including high-dose mortality and non-sustained expression,which require further optimization in future studies.展开更多
Functional studies have suggested the important role of early growth response I （EGR1） and Laminin a2- chain （LAMA,？.） in human eye development. Genetic studies have reported a significant association of the sing...Functional studies have suggested the important role of early growth response I （EGR1） and Laminin a2- chain （LAMA,？.） in human eye development. Genetic studies have reported a significant association of the single nu- cleotide polymorphism （SNP） in the LAMA2 gene with myopia. This study aimed to evaluate the association of the tagging SNPs （tSNPs） in the EGR1 and LAMA2 genes with high myopia in two independent Han Chinese populations. Four tSNPs （rs11743810 in the EGR1 gene; rs2571575, rs9321170, and rs1889891 in the LAMA2 gene） were se- lected, according to the HapMap database （http：//hapmap.ncbi.nlm.nih.gov）, and were genotyped using the ligase detection reaction （LDR） approach for 167 Hart Chinese nuclear families with extremely highly myopic offspring （〈-10.0 diopters） and an independent group with 485 extremely highly myopic cases （〈-10.0 diopters） and 499 con- trois. Direct sequencing was used to confirm the LDR results in twenty randomly selected subjects. Family-based association analysis was performed using the family-based association test （FBAT） software package （Version 1.5.5）. Population-based association analysis was performed using the Chi-square test. The association analysis power was estimated using online software （http：lldesign.cs.ucla.edu）. The FBAT demonstrated that all four tSNPs tested did not show association with high myopia （P〉0.05）. Haplotype analysis of tSNPs in the LAMA2 genes also did not show a significant association （P〉0.05）. Meanwhile, population-based association analysis also showed no significant asso- ciation results with high myopia （P〉0.05）. On the basis of our family- and population-based analyses for the Han Chinese population, we did not find positive association signals of the four SNPs in the LAMA2 and EGR1 genes with high myopia.展开更多
Pelvic organ prolapse (POP) is the descent of the pelvic organs,including bladder, uterus, vagina and rectum, resulting in pelvic discomfort, urinary and fecal incontinence and sexual dysfunction(1)The prevalence of s...Pelvic organ prolapse (POP) is the descent of the pelvic organs,including bladder, uterus, vagina and rectum, resulting in pelvic discomfort, urinary and fecal incontinence and sexual dysfunction(1)The prevalence of symptomatic POP in China is 9.56%according to a cross-sectional study involving 54,000 adult women in six provinces in the mainland of China (unpublished data). The etiology of this disorder is multifactorial, including race, age, body mass index(BMI), parity and menopause (1)The loss of the integrity of vaginal connective tissue has been demonstrated to weaken the pelvic floor support and promote the development of POP.展开更多
基金Supported by The Suzhou Science and Technology Development Plan Guiding Project,No.SZSYYXH-2023-YB5The Suzhou Science and Technology Development Plan Project,No.SKY2023002The Suzhou Key Laboratory of Children's Structural Deformities,No.SZS2022018.
文摘BACKGROUND We report a rare case of primary clinical presentation featuring elevated creatine kinase(CK)levels in a neonate,which is associated with the LAMA2 gene.In this case,a heterozygous mutation in exon5 of the LAMA2 gene,c.715C>G(resulting in a change of nucleotide number 715 in the coding region from cytosine to gua-nine),induced an amino acid alteration p.R239G(No.239)in the patient,repre-senting a missense mutation.This observation may be elucidated by the neonatal creatine monitoring mechanism,a phenomenon not previously reported.CASE SUMMARY We analysed the case of a neonate presenting solely with elevated CK levels who was eventually discharged after supportive treatment.The chief complaint was identification of increased CK levels for 15 d and higher CK values for 1 d.Ad-mission occurred at 18 d of age,and despite prolonged treatment with creatine and vitamin C,the elevated CK levels showed limited improvement.Whole exo-me sequencing revealed the presence of a c.715C>G mutation in LAMA2 in the newborn,correlating with a clinical phenotype.However,the available informa-tion offers insufficient evidence for clinical pathogenicity.CONCLUSION Mutations in LAMA2 are associated with the clinical phenotype of increased neonatal CK levels,for which no specific treatment exists.Whole genome sequen-cing facilitates early diagnosis.
基金This study received support from the following grants:National Natural Science Foundation of China(82171393 to H.X.)National High Level Hospital Clinical Research Funding(High Quality Clinical Research Project of Peking University First Hospital)(2022CR69 to H.X.)+4 种基金Natural Science Foundation of Beijing Municipality(7212116 to H.X.)National Key Research and Development Program of China(2016YFC0901505 to H.X.)Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases(BZ0317 to H.X.)Research Foundation for Youth Talents of the First Affiliated Hospital of Nanchang University(YFYPY202223 to D.T.)Natural Science Foundation of Beijing Municipality(7242149 to H.L.).
文摘LAMA2-related congenital muscular dystrophy(LAMA2-CMD),characterized by laminin-α2 deficiency,is debilitating and ultimately fatal.To date,no effective therapy has been clinically available.Laminin-a1,which shares significant similarities with laminin-a2,has been proven as a viable compensatory modifier.To evaluate its clinical applicability,we establish a Lama2 exon-3-deletion mouse model(dy^(H)/dy^(H)).The dy^(H)/dy^(H) mice exhibit early lethality and typical LAMA2-CMD phenotypes,allowing the evaluation of various endpoints.In dy^(H)/dy^(H) mice treated with synergistic activation mediator-based CRISPRa-mediated Lama1 upregulation,a nearly doubled median survival is observed,as well as improvements in weight and grip.Significant therapeutical effects are revealed by MRl,serum biochemical indices,and muscle pathology studies.Treating LAMA2-CMD with LAMA1 upregulation is feasible,and early intervention can alleviate symptoms and extend lifespan.Additionally,we reveal the limitations of LAMA1 upregulation,including high-dose mortality and non-sustained expression,which require further optimization in future studies.
基金Project supported by the Natural Science Foundation of Zhejiang Province(No.LY14H120003)the Qianjiang Talent Project of Zhejiang Province(No.2013R10040),China
文摘Functional studies have suggested the important role of early growth response I （EGR1） and Laminin a2- chain （LAMA,？.） in human eye development. Genetic studies have reported a significant association of the single nu- cleotide polymorphism （SNP） in the LAMA2 gene with myopia. This study aimed to evaluate the association of the tagging SNPs （tSNPs） in the EGR1 and LAMA2 genes with high myopia in two independent Han Chinese populations. Four tSNPs （rs11743810 in the EGR1 gene; rs2571575, rs9321170, and rs1889891 in the LAMA2 gene） were se- lected, according to the HapMap database （http：//hapmap.ncbi.nlm.nih.gov）, and were genotyped using the ligase detection reaction （LDR） approach for 167 Hart Chinese nuclear families with extremely highly myopic offspring （〈-10.0 diopters） and an independent group with 485 extremely highly myopic cases （〈-10.0 diopters） and 499 con- trois. Direct sequencing was used to confirm the LDR results in twenty randomly selected subjects. Family-based association analysis was performed using the family-based association test （FBAT） software package （Version 1.5.5）. Population-based association analysis was performed using the Chi-square test. The association analysis power was estimated using online software （http：lldesign.cs.ucla.edu）. The FBAT demonstrated that all four tSNPs tested did not show association with high myopia （P〉0.05）. Haplotype analysis of tSNPs in the LAMA2 genes also did not show a significant association （P〉0.05）. Meanwhile, population-based association analysis also showed no significant asso- ciation results with high myopia （P〉0.05）. On the basis of our family- and population-based analyses for the Han Chinese population, we did not find positive association signals of the four SNPs in the LAMA2 and EGR1 genes with high myopia.
基金supported by the Chinese Academy of Medical Sciences Initiative for Innovative Medicine (CAMS-2017-I2M-1002)
文摘Pelvic organ prolapse (POP) is the descent of the pelvic organs,including bladder, uterus, vagina and rectum, resulting in pelvic discomfort, urinary and fecal incontinence and sexual dysfunction(1)The prevalence of symptomatic POP in China is 9.56%according to a cross-sectional study involving 54,000 adult women in six provinces in the mainland of China (unpublished data). The etiology of this disorder is multifactorial, including race, age, body mass index(BMI), parity and menopause (1)The loss of the integrity of vaginal connective tissue has been demonstrated to weaken the pelvic floor support and promote the development of POP.
