OBJECTIVE: To carry out genetic testing and clinical phenotypic characterization on a four-generation Chinese pedigree affected with Stickler syndrome type I and explore its genotype-phenotype correlation. METHODS: A child presented at the Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine in February 2023 for micrognathia, glossoptosis and cleft palate and his family members were selected as the study subjects. Clinical data were collected from the affected members, and peripheral blood samples were obtained from 17 participants (including 4 patients and 13 asymptomatic individuals). Whole exome sequencing (WES) was carried out. Candidate variant was verified by Sanger sequencing. Genotype-phenotype correlation was analyzed by integrating the sequencing data with evidence from existing literature. This study has bee granted by the Ethics Committee of Guangdong Provincial Hospital of Traditional Chinese Medicine and Guangzhou Women and Children's Medical Center (Ethics No.: 2022-406B00). RESULTS: The four-generation pedigree has comprised 19 members. In addition to the proband, 5 affected individuals had manifested with high myopia, congenital cataracts, and progressive vision loss. Two deceased members reportedly exhibited similar ocular manifestations. Among the four living patients, two had developed retinal detachment, while two others presented with chronic joint pain onset between 35 ~ 40 years of age. One patient required hip replacement surgery at age 42 secondary to femoral head necrosis. The proband, the youngest affected member, exhibited characteristic phenotypes including congenital micrognathia and cleft palate, consistent with Pierre-Robin syndrome. Genetic analysis revealed a heterozygous nonsense mutation in COL2A1 (NM_001844.5: c.2668C>T; p.Gln890Ter) segregating with the disease in all four symptomatic patients. This variant was absent in asymptomatic family members and unaffected controls. While the mutation is listed in ClinVar, no clinical case report has associated it with this phenotypic spectrum. It was not recorded in population databases (gnomAD v4.1.0, 1000 Genomes Project, or ExAC), supporting its potential pathogenicity. CONCLUSION This study has diagnosed a four-generation Chinese pedigree with Stickler syndrome type I attributed to the pathogenic COL2A1 variant c.2668C>T (p.Gln890Ter), which is a rare nonsense mutation associated with ocular predominance and variable skeletal involvement. Notably, this family exhibited marked clinical heterogeneity despite sharing the identical genotype, which highlighted the challenges in phenotype-genotype correlation. The autosomal dominant transmission pattern observed in this pedigree has provided critical insights into COL2A1-related collagenopathies and underscored the necessity of ultrasonographic monitoring for ocular anomalies during prenatal diagnosis. Above findings have advanced our understanding of the pleiotropic effects in type Ⅱ collagen disorders and laid the foundation for precision-based genetic counseling, enabling targeted cascade screening and implementation of tertiary prevention strategies against congenital disabilities for high-risk families.
Adolescent ; Adult ; Child ; Child, Preschool ; Female ; Humans ; Male ; Middle Aged ; Arthritis/genetics* ; Collagen Type II/genetics* ; Connective Tissue Diseases/genetics* ; Exome Sequencing ; Genetic Association Studies ; Genotype ; Hearing Loss, Sensorineural/genetics* ; Mutation ; Pedigree ; Phenotype ; Retinal Detachment/genetics* ; East Asian People/genetics*

Stickler syndrome is a genetically heterogeneous disorder that affects the ocular, auditory, and musculoskeletal systems. Ocular-only variant of Stickler syndrome type 1 (OSTL1) is characterized by high risk of retinal detachment without systemic involvement and is caused by alternatively spliced exon 2 mutation of COL2A1. We report the cases of two Korean families with OSTL1 carrying likely pathogenic variants of COL2A1. All patients presented with membranous vitreous anomaly, peripheral retinal degeneration, and/or rhegmatogenous retinal detachment, but no systemic manifestations. By genetic analysis, two likely pathogenic non-exon 2 variants, c.2678dupC (p.Ala895Serfs*49) and c.3327+ 1G>C, were identified in COL2A1. Our results demonstrate that COL2A1 defects in OSTL1 are not confined to mutations in exon 2. Together with molecular data, ophthalmologists should consider genetic diagnosis of Stickler syndrome in patients with vitreous anomaly to prevent blindness from retinal detachment. To our knowledge, this is the first report of genetically confirmed OSTL1 in Korea.
Adult ; Arthritis/*genetics/pathology ; Asian Continental Ancestry Group/*genetics ; Base Sequence ; Collagen Type II/*genetics ; Connective Tissue Diseases/*genetics/pathology ; DNA Mutational Analysis ; Exons ; Female ; Hearing Loss, Sensorineural/*genetics/pathology ; Humans ; Male ; Middle Aged ; Republic of Korea ; Retinal Detachment/*genetics/pathology ; Visual Acuity

OBJECTIVETo evaluate the effect of Notoginseng Radix on hepatic expression of transforming growth factor beta1 (TGF-beta1) and connective tissue growth factor (CTGF) in rats with alcoholic liver disease (ALD), in order to discuss its protective effect on alcoholic cirrhosis.

METHODFifty SD male rats were divided into the normal control group, the model group, the high-dose and low-dose Notoginseng Radix groups (3.0, 12.0 g x kg(-1)) and the magnesium isoglycyrrhizinate group (24 mg x kg(-1)), with 10 rats in each group. Apart from the control group, other groups were administered with ethanol-cornoil-pyrazole for 14 weeks to establish the alcoholic liver disease model. During the establishment of the model, the high-dose and low-dose Notoginseng Radix groups were administered with 12 g x kg(-1) x d(-1) Notoginseng Radix for 14 weeks, once everyday. Efforts were made to detect liver function, pathology with Masson staining, and the expressions of TGF-beta1, Smad3, Smad7 and CTGF mRNA.

RESULTCompared with the rats in model group, rats in Notoginseng Radix groups showed significant reduction in liver ALT, AST, collagen fiber deposition, and TGF-beta1, Smad3 and CTGF mRNA expressions in liver tissues, with the increase in the expression quantity of Smad7 mRNA. There were differences between the Notoginseng Radix groups. No significant difference was observed between the high-dose Notoginseng Radix group and the magnesium isoglycyrrhizinate group.

CONCLUSIONNotoginseng Radix can affect TGF-beta1/Smads signaling pathway and reduce the expression of CTGF.

Animals ; Connective Tissue Growth Factor ; genetics ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; Gene Expression ; drug effects ; Humans ; Liver Diseases, Alcoholic ; drug therapy ; genetics ; metabolism ; Male ; Panax notoginseng ; chemistry ; Rats ; Rats, Sprague-Dawley ; Smad3 Protein ; genetics ; metabolism ; Smad7 Protein ; genetics ; metabolism ; Transforming Growth Factor beta1 ; genetics ; metabolism

OBJECTIVE: To determine the expression and effect of hypoxia-inducible factor 1alpha (HIF-1alpha) in chronic kidney fibrosis, and to observe the effect of perindopril on its expression. METHODS: The rat models of chronic kidney fibrosis were induced by 5/6 nephrectomy, and 11 successful 5/6-nephrectomized rats were randomly assigned to 2 groups: a surgery group (n=6) and a treatment group (perindopril, n=5). A control group was induced by sham operation. Five weeks later, Picro-Sirius red stained was applied to measure collagen in the kidney, and Western blot was used to test HIF-1alpha protein; The expression of HIF-1alpha and CTGF mRNA in the kidney was analyzed by real-time PCR. RESULTS: Picro-Sirius red stained revealed significant accumulation of collagens in the surgery group than the control group; and lower accumulation of collagens in the treatment group than the surgery group. Western blot showed higher deposit HIF-1alpha in the surgery group than the control group (P<0.01) and lower deposit HIF-1alpha in the treatment group than the surgery group (P<0.01). Real time PCR showed higher expression of HIF-1alpha and CTGF mRNA in the surgery group than the control group (P<0.01)and lower expression of HIF-1alpha and CTGF mRNA in kidney of the treatment group compared with the surgery group (P<0.01). The expression of CTGF had positive correlation with HIF-1alpha (r=0.68, P<0.01). CONCLUSION The HIF-1alpha may induce kidney fibrosis through CTGF. Perindopril may decrease the expression of HIF-1alpha and CTGF to ameliorate kidney fibrosis.
Animals ; Connective Tissue Growth Factor ; genetics ; metabolism ; Fibrosis ; metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit ; genetics ; metabolism ; Kidney ; pathology ; Kidney Diseases ; drug therapy ; etiology ; metabolism ; Male ; Nephrectomy ; Perindopril ; pharmacology ; therapeutic use ; RNA, Messenger ; genetics ; metabolism ; Random Allocation ; Rats ; Rats, Sprague-Dawley