BACKGROUND: Weill-Marchesani syndrome (WMS) is a hereditary connective tissue disorder with substantial heterogeneity in clinical features and genetic etiology, so it is essential to define the full mutation spectrum for earlier diagnosis. In this study, we report Weill-Marchesani-like syndrome (WMS-like) change to autosomal dominance inheritance caused by novel haplotypic mutations in latent transforming growth factor beta-binding protein 2 (LTBP2).
METHODS: Twenty-five members from a 4-generation Chinese family were recruited from Guangzhou, of whom nine were diagnosed with WMS-like disease, nine were healthy, and seven were of \"uncertain\" clinical status because of their young age. All members received detailed physical and ocular examinations. Whole-exome sequencing, Sanger sequencing, and real-time PCR were used to identify and verify the causative mutations in family members.
RESULTS: Genetic sequencing revealed novel haplotypic mutations on the same LTBP2 chromosome associated with WMS-like, c. 2657C>A/p.T886K in exon 16 and deletion of exons 25-36. Real-time PCR and Sanger sequencing verified both mutations in patients with clinically diagnosed WMS-like, and in one \"uncertain\" child. In these patients, the haplotypic mutations led to ectopia lentis, short stature, and obesity.
CONCLUSIONS: Our study revealed that WMS-like may be associated with haplotypic LTBP2 mutations with autosomal dominant inheritance.

The objective of this study is to investigate whether common genetic variants of the LTBP4 gene are linked to the susceptibility of sudden cardiac death in individuals who have atherosclerotic coronary artery disease (SCD-CAD) in Chinese populations. A total of 208 SCD-CAD cases and 638 controls were included in the analysis, and logistic regression was employed to assess the association between a 4-bp insertion/deletion polymorphism (rs34005443) within LTBP4 and the susceptibility to SCD-CAD among Chinese individuals. Logistic regression analysis demonstrated a notable association between the insertion allele of rs34005443 and an escalated susceptibility to SCD-CAD [odds ratio (OR) = 1.434; 95 % confidence interval:1.14-1.80; P = 1.79 × 10-3]. Genotype-phenotype correlation analysis was performed using Genotype-Tissue expression (GTEx) database and further validated by human myocardium using qPCR. Correlation analysis revealed that LTBP4 expression level was lower in samples with the insertion allele. Furthermore, the dual-luciferase activity assays indicated that rs34005443 may play a regulatory role. Additionally, we predicted 30 transcription factors that are likely to bind to rs34005443 and its highly linked genetic variants via 3DSNP database. Subsequent GO and KEGG analysis indicated that these transcription factors have a significant function in regulating gene expression. Finally, PPI network analysis suggested a tight connection between LTBP4 proteins and TGFβs, highlighting these genes as potential hub genes in the context of SCD-CAD. In summary, our study revealed that rs34005443 might contribute to SCD-CAD susceptibility by regulating LTBP4 expression. These findings revealed that this indel could be a potentially functional marker for molecular diagnosis and risk stratification of SCD-CAD.

Senescent kidney can lead to the maladaptive repairment and predispose age-related kidney diseases. Here, we explore the renal anti-senescence effect of a known kind of drug, sodium-dependent glucose transporters 2 inhibitor (SGLT2i). After 4 months intragastrically administration with dapagliflozin on senescence-accelerated mouse prone 8 (SAMP8) strain mice, the physiologically effects (lowering urine protein, enhancing glomerular blood perfusion, inhibiting expression of senescence-related biomarkers) and structural changes (improving kidney atrophy, alleviating fibrosis, decreasing glomerular mesangial proliferation) indicate the potential value of delaying kidney senescence of SGLT2i. Senescent human proximal tubular epithelial (HK-2) cells induced by H2 O2 also exhibit lower senescent markers after dapagliflozin treatment. Further mechanism exploration suggests LTBP2 have the great possibility to be the target for SGLT2i to exert its renal anti-senescence role. Dapagliflozin down-regulate the LTBP2 expression in kidney tissues and HK-2 cells with senescent phenotypes. Immunofluorescence staining show SGLT2 and LTBP2 exist colocalization, and protein-docking analysis implies there is salt-bridge formation between them; these all indicate the possibility of weak-interaction between the two proteins. Apart from reducing LTBP2 expression in intracellular area induced by H2 O2 , dapagliflozin also decrease the concentration of LTBP2 in cell culture medium. Together, these results reveal dapagliflozin can delay natural kidney senescence in non-diabetes environment; the mechanism may be through regulating the role of LTBP2.

LTBP1 is closely related to TGF-β1 function as an essential component, which was unclear in gastric cancer (GC). Harbin Medical University (HMU)-GC cohort and The Cancer Genome Atlas (TCGA) dataset were combined to form a training cohort to calculate the connection between LTBP1 mRNA expression, prognosis and clinicopathological features. The training cohort was also used to verify the biological function of LTBP1 and its relationship with immune microenvironment and chemosensitivity. In the tissue microarrays (TMAs), immunohistochemical (IHC) staining was performed to observe LTBP1 protein expression. The correlation between LTBP1 protein expression level and prognosis was also analyzed, and a nomogram model was constructed. Western blotting (WB) was used in cell lines to assess LTBP1 expression. Transwell assays and CCK-8 were employed to assess LTBP1\'s biological roles. In compared to normal gastric tissues, LTBP1 expression was upregulated in GC tissues, and high expression was linked to a bad prognosis for GC patients. Based on a gene enrichment analysis, LTBP1 was primarily enriched in the TGF-β and EMT signaling pathways. Furthermore, high expression of LTBP1 in the tumor microenvironment was positively correlated with an immunosuppressive response. We also found that LTBP1 expression (p = 0.006) and metastatic lymph node ratio (p = 0.044) were independent prognostic risk factors for GC patients. The prognostic model combining LTBP1 expression and lymph node metastasis ratio reliably predicted the prognosis of GC patients. In vitro proliferation and invasion of MKN-45 GC cells were inhibited and their viability was decreased by LTBP1 knockout. LTBP1 plays an essential role in the development and progression of GC, and is a potential prognostic biomarker and therapeutic target for GC.

The advent of proteomics offers an unprecedented opportunity to predict dementia onset. We examined this in data from 52,645 adults without dementia in the UK Biobank, with 1,417 incident cases and a follow-up time of 14.1 years. Of 1,463 plasma proteins, GFAP, NEFL, GDF15 and LTBP2 consistently associated most with incident all-cause dementia (ACD), Alzheimer\'s disease (AD) and vascular dementia (VaD), and ranked high in protein importance ordering. Combining GFAP (or GDF15) with demographics produced desirable predictions for ACD (area under the curve (AUC) = 0.891) and AD (AUC = 0.872) (or VaD (AUC = 0.912)). This was also true when predicting over 10-year ACD, AD and VaD. Individuals with higher GFAP levels were 2.32 times more likely to develop dementia. Notably, GFAP and LTBP2 were highly specific for dementia prediction. GFAP and NEFL began to change at least 10 years before dementia diagnosis. Our findings strongly highlight GFAP as an optimal biomarker for dementia prediction, even more than 10 years before the diagnosis, with implications for screening people at high risk for dementia and for early intervention.

To evaluate the frequency of LTBP2 mutations and to elaborate on LTBP2-related clinical phenotypes in a Chinese congenital ectopia lentis (CEL) cohort.
In total, 145 Chinese probands with CEL were recruited for this study and underwent ocular and systemic examinations. Whole-exome sequencing was used to identify mutations, and Sanger sequencing and bioinformatics analysis were further performed to verify pathogenic mutations.
Overall, biallelic mutations in LTBP2 involving eight novel mutations (c.4370-7_4370-9delTCT, c.4370-5C>G, c.3452G>A, c.2253delG, c.4114T>C, c.1251G>A, c.4760G>A, and c.620G>A) were identified in four CEL probands (4/145, 2.76%). Patients with LTBP2 mutations were characterized by a megalocornea, spherophakia, high myopia, and glaucoma instead of a flat cornea, high corneal astigmatism, cardiovascular and skeletal abnormalities that were reported in other gene mutations. A novel homozygous frameshift mutation was detected, and this type of mutation was found to cause more complicated ocular symptoms than others, ranging from the anterior segment to the fundus.
This study reported the mutation frequency of the LTBP2 gene in a Chinese CEL cohort and provided novel insight into LTBP2-related genotype-phenotype associations in CEL.

UNASSIGNED: To extend the mutation spectrum and explore the characteristics of genotypes and ocular phenotypes in ectopia lentis (EL).
UNASSIGNED: Variants in all 14 reported EL-associated genes were selected from in-house data sets as well as literature review, and available clinical data were analyzed.
UNASSIGNED: Likely pathogenic variants in three genes were identified in 156 unrelated families with EL from the in-house cohort, of which 97.4% resulted from variants in FBN1, whereas the remaining were caused by variants in ADAMTSL4 (1.3%) and LTBP2 (1.3%). A comparative analysis of the in-house data and literature review suggested several characteristics: (1) a higher proportion of cysteine involvement variants in FBN1, either variants introducing or eliminating cysteine, and an earlier diagnosis age were presented in our cohort than in published literature; (2) the axial length (AL) and refractive error increased more rapidly with age in preschool EL children than normal children, and the increased rate of AL was slower in patients with surgery than those without surgery; (3) aberrant astigmatism was common in EL; and (4) worse vision and earlier onset age were observed in patients with non-FBN1 variants (all P < 0.05).
UNASSIGNED: Variants in FBN1 are the predominant cause of EL, with the most common cysteine involvement variants. Early-stage EL manifests refractive error but gradually converts to axial myopia through defocus introduced by lens dislocation. Aberrant astigmatism is a suggestive sign of EL. Non-FBN1 variants cause early-onset and severe phenotypes. These results provide evidence for early diagnosis as well as timely treatment for EL.

Few biomarkers distinguish connective tissue disease-associated interstitial lung disease (CTD-ILD) from idiopathic pulmonary fibrosis (IPF). Latent transforming growth factor-β binding protein-2 (LTBP2), a secreted extracellular matrix protein, is involved in pulmonary fibrosis. However, the role of LTBP2 in differentially diagnosing CTD-ILD and IPF is unclear. In this study, enzyme-linked immunosorbent assays quantified plasma LTBP2 concentrations in 200 individuals (35 healthy controls, 42 CTD patients without ILD, 89 CTD-ILD patients, and 34 IPF patients). CTD-ILD and IPF were further classified based on chest imaging pattern and pulmonary function test results. Plasma LTBP2 levels were significantly elevated in the IPF group compared with the CTD-ILD group. ROC analysis further suggested the possible value of LTBP2 in differentially diagnosing CTD-ILD and IPF. Additionally, CTD-ILD patients with progressive lung fibrosis had higher plasma LTBP2 concentrations than those who did not. Similarly, patients with IPF developing acute exacerbation showed higher plasma LTBP2 levels than those with stable IPF. This is the first study showing that LTBP2 was closely associated with the usual interstitial pneumonia (UIP) pattern in rheumatoid arthritis-associated ILD (RA-ILD). Moreover, the optimal cutoff values of LTBP2 for distinguishing IPF from CTD-UIP/RA-UIP were 33.75 and 38.33 ng/mL with an AUC of 0.682 and 0.681, respectively. Our findings suggest that plasma LTBP2 levels may differentially diagnose CTD-ILD and IPF, and assess their fibrotic activity. Additionally, clinical LTBP2 evaluation may be a great aid to identifying the presence of the UIP pattern in RA-ILD and to discriminating IPF from CTD-UIP, particularly RA-UIP.

Weill-Marchesani syndrome (WMS) manifests as ectopia lentis (EL), microspherophakia and short stature, which is caused by ADAMTS10, LTBP2, or ADAMTS17 gene defects. This study aims to investigate the characteristics and genotype-phenotype correlations of WMS with ADAMTS17 mutations. WMS patients with ADAMTS17 variants were identified by whole-exome sequencing from 185 patients with EL. All the included patients underwent comprehensive ocular and systemic examinations. ADAMTS17 variants were reviewed from included patients, published literature, and public databases. Bioinformatics analysis, co-segregation analysis, species sequence analysis, and protein silico modeling were used to verify the pathogenic mutations. A total of six novel ADAMTS17 mutations (c.1297C > T, c.2948C > T, c.1322+2T > C, c.1716C > G, c.1630G > A, and c.1669C > T) were identified in four WMS probands in our EL cohort (4/185, 2.16%). All probands and their biological parents presented with apparent short stature compared with the standard value. In particular, one child was detected with valvular heart disease, which has not previously been reported in patients with ADAMTS17 mutations. Conserved residues were greatly affected by the substitution of amino acids caused by these six mutations. Short stature could be considered a clue for EL patients with ADAMTS17 mutations, and much more attention needs to be paid to heart disorders among these patients. This study not only reported the characteristics of ADAMTS17 mutation-related WMS but also helped to recognize the genotype-phenotype correlations in these patients.

We report 3 novel variants in fibrillin-1 (FBN1) and latent transforming growth factor-β-binding protein 2 (LTBP2) in 3 families with isolated ectopia lentis (EL), which shed new light on the diagnosis and genetic counseling of EL and secondary glaucoma in clinical settings.
To explore the genetic mechanism in 3 families with isolated EL and secondary angle closure glaucoma.
Three Han Chinese families with EL and glaucoma were recruited. All of the participants underwent complete ocular and general physical examinations and DNA samples were extracted from peripheral venous blood and screened for disease-causing variants using whole exome and Sanger sequencing. In silico analyses were performed to predict the structural and functional changes in gene variants and abnormal proteins.
All 3 probands presented with EL and pupillary-blocking glaucoma. Genetic testing showed that all the patients have zonule-related gene mutations, with the proband (II:1), as well as his mother (I:2) and daughters (III:1 and III:2) from family 1 carrying a heterozygous mutation in FBN1 gene (c.6493G>T:p.(V2165L)); the proband (II:1) from family 2 carrying a heterozygous mutation in FBN1 gene (c.2543C>A:p.(T848N)), and the proband (II:1) from family 3 carrying a pair of compound heterozygous mutations in LTBP2 gene (c.4825T>A:p.(C1609S) / c.529T>C:p.(W177R)). No other genetic variants were found to be associated with the phenotypes of patients and other family members in this study. All variants are predicted to affect the structure and function of proteins as risk factors for EL based on bioinformatics analysis.
Four novel mutations were identified in 3 families with EL, suggesting an intimate link between specific mutations in FBN1 and LTBP2 and isolated EL and angle closure glaucoma. Our results expanded the variant spectrum of zonule-related genes and helped explore the underlying molecular pathology of these disorders.