Familial acne inversa (AI) is an autoinflammatory disorder that affects hair follicles and is caused by loss-of-function mutations in y-secretase component genes.We and other researchers showed that nicastrin (NCSTN) ...Familial acne inversa (AI) is an autoinflammatory disorder that affects hair follicles and is caused by loss-of-function mutations in y-secretase component genes.We and other researchers showed that nicastrin (NCSTN) is the most frequently mutated gene in familial AI.In this study,we generated a keratin 5-Cre-driven epidermis-specific Ncstn conditional knockout mutant in mice.We determined that this mutant recapitulated the major phenotypes of AI,including hyperkeratosis of hair follicles and inflammation.In Ncstnflox/flox;K5-Cre mice,the IL-36a expression level markedly increased starting from postnatal day 0 (P0),and this increase occurred much earlier than those of TNF-α,IL-23A,IL-1 3,and TLR4.RNA-Seq analysis indicated that Sprr2d,a member of the small proline-rich protein 2 family,in the skin tissues of the Ncstnflox/flox,;K5-Cre mice was also upregulated on P0.Quantitative reverse-transcription polymerase chain reaction showed that other Sprr2 genes had a similar expression pattern.Our findings suggested that IL-36a might be a key inflammatory cytokine in the pathophysiology of AI and implicate malfunction of the skin barrier in the pathogenesis of AI.展开更多
Background: Medullary cystic kidney disease (MCKD) is clinically indistinguishable from several other autosomal-dominant renal diseases: thus, molecular genetic testing is needed to establish a definitive diagnosi...Background: Medullary cystic kidney disease (MCKD) is clinically indistinguishable from several other autosomal-dominant renal diseases: thus, molecular genetic testing is needed to establish a definitive diagnosis. A specific type of single cytosine insertion in the variable number tandem repeat (VNTR) of the mucin 1 (MUC1) gene is the only known cause of MCKD1; however, genetic analysis of this mutation is difficult and not yet offered routinely. To identify the causative mutation/s and establish a definitive diagnosis in a Chinese family with chronic kidney disease, clinical assessments and genetic analysis were performed, including using a modified genotyping method to identify the MUC1-VNTR single cytosine insertion. Methods: Clinical data from three patients in a Chinese family with chronic kidney disease were collected and evaluated. Linkage analysis was used to map the causative locus. Mutation analysis of uromodulin (UMOD) gene was performed using polymerase chain reaction (PCR) and direct sequencing. For MUC1 genotyping, the mutant repeat units were enriched by Mwol restriction, and then were amplified and introduced into pMD-18T vectors. The 192 clones per transformant were picked up and tested by colony PCR and second round of Mwol digestion. Finally, Sanger sequencing was used to confirm the MUC1 mutation. Results: Clinical findings and laboratory results were consistent with a tubulointerstitial lesion. Linkage analysis indicated that the family was compatible with the MCKDI locus. No mutations were found in UMOD gene. Using the modified MUC1 genotyping method, we detected the MUC1-VNTR single cytosine insertion events in three patients of the family; and mutation-containing clones were 12/192, 14/192, and 5/96, respectively, in the three patients. Conclusions: Clinical and genetic findings could support the MCKDI diagnosis. The modified strategy has been demonstrated to be a practical way to detect MUCI mutation.展开更多
Dear Editor,Craniofacial microsomia(CFM,MIM#164210)is a congenital malformation involving the first and second branchial arch derivatives.The phenotype of CFM is highly variable and typically affects the external ear,...Dear Editor,Craniofacial microsomia(CFM,MIM#164210)is a congenital malformation involving the first and second branchial arch derivatives.The phenotype of CFM is highly variable and typically affects the external ear,middle ear,mandible and temporomandibular joint,and facial muscles on the affected side.Accompanied by craniofacial anomalies,cardiac,vertebral,and central nervous system defects may occur.Microtia is considered the minimum diagnostic criterion[1,2].展开更多
Marfan syndrome(MFS) is a systemic connective tissue disease principally affecting the ocular, skeletal and cardiovascular systems. This autosomal dominant disorder carries a prevalence of 1:3,000 to 1:5,000. This stu...Marfan syndrome(MFS) is a systemic connective tissue disease principally affecting the ocular, skeletal and cardiovascular systems. This autosomal dominant disorder carries a prevalence of 1:3,000 to 1:5,000. This study aims to define the mutational spectrum of MFS related genes in Chinese patients and to establish genotype-phenotype correlations in MFS. Panel-based targeted next-generation sequencing was used to analyze the FBN1, TGFBR1 and TGFBR2 genes in 123 unrelated Chinese individuals with MFS or a related disease. Genotype-phenotype correlation analyses were performed in mutation-positive patients. The results showed that 97 cases/families(78.9%;97/123) harbor at least one(likely) pathogenic mutation, most of which were in FBN1;four patients had TGFBR1/2 mutations;and one patient harbored a SMAD3 mutation. Three patients had two FBN1 mutations, and all patients showed classical MFS phenotypes. Patients with a dominant negative-FBN1 mutation had a higher prevalence of ectopia lentis(EL). Patients carrying a haploinsufficiency-FBN1 mutation tended to have aortic dissection without EL. This study extends the spectrum of genetic backgrounds of MFS and enriches our knowledge of genotype-phenotype correlations.展开更多
To the Editor:The human four and a half LIM domain 1 (FHL1) gene,located on Xq26.3,encodes for a protein with only LIM domains.LIM domains,named after their initial discovery in the proteins Lin11,Isl-1,and Mec-3,a...To the Editor:The human four and a half LIM domain 1 (FHL1) gene,located on Xq26.3,encodes for a protein with only LIM domains.LIM domains,named after their initial discovery in the proteins Lin11,Isl-1,and Mec-3,are cysteine-rich protein motifs composed of two contiguous zinc finger domains separated by a two-amino acid residue hydrophobic linker.展开更多
Background:H syndrome (OMIM 612391) is a recently described autosomal recessive genodermatosis characterized by indurated hyperpigmented and hypertrichotic skin,as well as other systemic manifestations.Most of the ...Background:H syndrome (OMIM 612391) is a recently described autosomal recessive genodermatosis characterized by indurated hyperpigmented and hypertrichotic skin,as well as other systemic manifestations.Most of the cases occurred in the Middle East areas or nearby countries such as Spain or India.The syndrome is caused by mutations in solute carrier family 29,member 3 (SLC29A3),the gene encoding equilibrative nucleoside transporter 3.The aim of this study was to identify pathogenic SLC29A 3 mutations in a Chinese patient clinically diagnosed with H syndrome.Methods:Peripheral blood samples were collected from the patient and his parents.Genomic DNA was isolated by the standard method.All six SLC29A3 exons and their flanking intronic sequences were polymerase chain reaction (PCR)-amplified and the PCR products were subjected to direct sequencing.Results:The patient,an 18-year-old man born to a nonconsanguineous Chinese couple,had more extensive cutaneous lesions,involving both buttocks and knee.In his genomic DNA,we identified a novel homozygous insertion-deletion,c.1269_1270delinsA,in SLC29A3.Both of his parents were carriers of the mutation.Conclusions:We have identified a pathogenic mutation in a Chinese patient with H syndrome.展开更多
基金This work was financially supported by the National Key Research and Development Program of China(No.2016Y FC0905100)the CAMS Innovation Fund for Medical Sciences(No.2016-I2M-1-002)+3 种基金the National Natural Science Foundation of China(NSFCNos.81788101 and 81230015)the Beijing Municipal Science and Technology Commission(No.Z151100003915078)for Xue Zhangby the National NSFC(No.31271345)for Yaping Liu.
文摘Familial acne inversa (AI) is an autoinflammatory disorder that affects hair follicles and is caused by loss-of-function mutations in y-secretase component genes.We and other researchers showed that nicastrin (NCSTN) is the most frequently mutated gene in familial AI.In this study,we generated a keratin 5-Cre-driven epidermis-specific Ncstn conditional knockout mutant in mice.We determined that this mutant recapitulated the major phenotypes of AI,including hyperkeratosis of hair follicles and inflammation.In Ncstnflox/flox;K5-Cre mice,the IL-36a expression level markedly increased starting from postnatal day 0 (P0),and this increase occurred much earlier than those of TNF-α,IL-23A,IL-1 3,and TLR4.RNA-Seq analysis indicated that Sprr2d,a member of the small proline-rich protein 2 family,in the skin tissues of the Ncstnflox/flox,;K5-Cre mice was also upregulated on P0.Quantitative reverse-transcription polymerase chain reaction showed that other Sprr2 genes had a similar expression pattern.Our findings suggested that IL-36a might be a key inflammatory cytokine in the pathophysiology of AI and implicate malfunction of the skin barrier in the pathogenesis of AI.
文摘Background: Medullary cystic kidney disease (MCKD) is clinically indistinguishable from several other autosomal-dominant renal diseases: thus, molecular genetic testing is needed to establish a definitive diagnosis. A specific type of single cytosine insertion in the variable number tandem repeat (VNTR) of the mucin 1 (MUC1) gene is the only known cause of MCKD1; however, genetic analysis of this mutation is difficult and not yet offered routinely. To identify the causative mutation/s and establish a definitive diagnosis in a Chinese family with chronic kidney disease, clinical assessments and genetic analysis were performed, including using a modified genotyping method to identify the MUC1-VNTR single cytosine insertion. Methods: Clinical data from three patients in a Chinese family with chronic kidney disease were collected and evaluated. Linkage analysis was used to map the causative locus. Mutation analysis of uromodulin (UMOD) gene was performed using polymerase chain reaction (PCR) and direct sequencing. For MUC1 genotyping, the mutant repeat units were enriched by Mwol restriction, and then were amplified and introduced into pMD-18T vectors. The 192 clones per transformant were picked up and tested by colony PCR and second round of Mwol digestion. Finally, Sanger sequencing was used to confirm the MUC1 mutation. Results: Clinical findings and laboratory results were consistent with a tubulointerstitial lesion. Linkage analysis indicated that the family was compatible with the MCKDI locus. No mutations were found in UMOD gene. Using the modified MUC1 genotyping method, we detected the MUC1-VNTR single cytosine insertion events in three patients of the family; and mutation-containing clones were 12/192, 14/192, and 5/96, respectively, in the three patients. Conclusions: Clinical and genetic findings could support the MCKDI diagnosis. The modified strategy has been demonstrated to be a practical way to detect MUCI mutation.
基金supported by the CAMS Innovation Fund for Medical Sciences (No.2021-I2M-1-052)the Research Funds from CAMS Plastic Surgery Hospital (Nos.YS202036 and YS202003).
文摘Dear Editor,Craniofacial microsomia(CFM,MIM#164210)is a congenital malformation involving the first and second branchial arch derivatives.The phenotype of CFM is highly variable and typically affects the external ear,middle ear,mandible and temporomandibular joint,and facial muscles on the affected side.Accompanied by craniofacial anomalies,cardiac,vertebral,and central nervous system defects may occur.Microtia is considered the minimum diagnostic criterion[1,2].
基金supported by the National Natural Science Foundation of China (81400187 and 81230015)CAMS Innovation Fund for Medical Sciences (2016-I2M-1-002)+1 种基金the Beijing Municipal Science and Technology Commission (Z151100003915078)the Special Research Fund for Central Public Scientific Research Institutes, Peking Union Medical College (2016ZX310160)
文摘Marfan syndrome(MFS) is a systemic connective tissue disease principally affecting the ocular, skeletal and cardiovascular systems. This autosomal dominant disorder carries a prevalence of 1:3,000 to 1:5,000. This study aims to define the mutational spectrum of MFS related genes in Chinese patients and to establish genotype-phenotype correlations in MFS. Panel-based targeted next-generation sequencing was used to analyze the FBN1, TGFBR1 and TGFBR2 genes in 123 unrelated Chinese individuals with MFS or a related disease. Genotype-phenotype correlation analyses were performed in mutation-positive patients. The results showed that 97 cases/families(78.9%;97/123) harbor at least one(likely) pathogenic mutation, most of which were in FBN1;four patients had TGFBR1/2 mutations;and one patient harbored a SMAD3 mutation. Three patients had two FBN1 mutations, and all patients showed classical MFS phenotypes. Patients with a dominant negative-FBN1 mutation had a higher prevalence of ectopia lentis(EL). Patients carrying a haploinsufficiency-FBN1 mutation tended to have aortic dissection without EL. This study extends the spectrum of genetic backgrounds of MFS and enriches our knowledge of genotype-phenotype correlations.
文摘To the Editor:The human four and a half LIM domain 1 (FHL1) gene,located on Xq26.3,encodes for a protein with only LIM domains.LIM domains,named after their initial discovery in the proteins Lin11,Isl-1,and Mec-3,are cysteine-rich protein motifs composed of two contiguous zinc finger domains separated by a two-amino acid residue hydrophobic linker.
文摘Background:H syndrome (OMIM 612391) is a recently described autosomal recessive genodermatosis characterized by indurated hyperpigmented and hypertrichotic skin,as well as other systemic manifestations.Most of the cases occurred in the Middle East areas or nearby countries such as Spain or India.The syndrome is caused by mutations in solute carrier family 29,member 3 (SLC29A3),the gene encoding equilibrative nucleoside transporter 3.The aim of this study was to identify pathogenic SLC29A 3 mutations in a Chinese patient clinically diagnosed with H syndrome.Methods:Peripheral blood samples were collected from the patient and his parents.Genomic DNA was isolated by the standard method.All six SLC29A3 exons and their flanking intronic sequences were polymerase chain reaction (PCR)-amplified and the PCR products were subjected to direct sequencing.Results:The patient,an 18-year-old man born to a nonconsanguineous Chinese couple,had more extensive cutaneous lesions,involving both buttocks and knee.In his genomic DNA,we identified a novel homozygous insertion-deletion,c.1269_1270delinsA,in SLC29A3.Both of his parents were carriers of the mutation.Conclusions:We have identified a pathogenic mutation in a Chinese patient with H syndrome.