The aim of this study was to investigate a novel FBN1 gene mutation in a pediatric patient with Marfan syndrome (MFS) to provide a theoretical basis for genetic counseling. The subject was a 5-month-old male infant. With informed consent from the proband and his family, 2 mL of peripheral venous blood was collected from the patient, his father, mother, and sister. DNA was extracted using a DNA extraction kit with EDTA-K as an anticoagulant. The extracted DNA was subjected to minigene transcription and bioinformatics analysis. For minigene construction, wild-type and mutant minigenes were inserted into pcMINI and pcMINI-C vectors, respectively. Four recombinant vectors were transfected into the HeLa and 293T cell lines. After transfection for 48 hours, RNA was extracted from eight samples. DNA was also extracted from the family members\' samples to construct a library. Target regions were captured using the SureSelect Human All Exon V6 (Agilent) kit and were sequenced with Illumina NovaSeq (sequencing read length 2×150 bp). Bioinformatic analysis identified the c.8226+5del mutation as a variant of uncertain clinical significance (VOUS). Literature and database reviews confirmed that this mutation had not been previously reported, identifying it as a novel mutation. The study identified a novel FBN1 mutation, c.8226+5del, that may be associated with clinical features such as low-set ears and distinctive facial characteristics in the proband. This mutation likely affects normal mRNA splicing, altering the structure and function of Exon 64 and potentially contributing to the development of autosomal dominant MFS.

OBJECTIVE: To investigate the relationship between visual prognosis and genotype in patients undergoing lens surgery for congenital ectopia lentis (EL).
METHODS: Prospective clinical cohort study.
METHODS: Patients with congenital EL who underwent lens removal and intraocular lens implantation received panel-based next-generation sequencing. Patients were grouped into children and adolescents/adults based on the age at surgery. The visual prognosis, including best-corrected visual acuity (BCVA) and amblyopia, was stratified into short-term and medium to long-term.
RESULTS: This study included 329 probands with congenital EL, with a median age at lens surgery of 7.00 years (interquartile range [IQR] = 5.00, 12.50 years). Children with the non-FBN1 mutation exhibited inferior medium to long-term postoperative BCVA (0.26 [IQR: 0.14, 0.33] vs 0.15 [IQR: 0.10, 0.22], P = .034) and a higher prevalence of amblyopia (44.4% vs 16.8%, P = .012) compared to those with FBN1 mutation. Multivariable analysis showed that genotype (FBN1 vs non-FBN1 mutation) was significantly associated with medium to long-term postoperative BCVA (b = -0.128, 95% CI -0.214 to -0.042, P = .004) and amblyopia (OR = 0.20, 95% CI 0.05-0.78, P = .020) in children. Further classification of FBN1 genotype did not yield significant correlations with visual prognosis. However, no significant correlation was observed between genotype and short-term visual prognosis in the children. Children with less severe EL (OR = 0.13, 95% CI 0.02-0.85, P = .033) had lower risks of amblyopia in the short-term follow-up. For adolescent and adult patients with congenital EL, those with poor preoperative BCVA and long axial length should be informed of suboptimal visual prognosis.
CONCLUSIONS: Genotype significantly influences the medium to long-term visual prognosis in children with congenital EL. Genotype, along with preoperative BCVA, may assist in establishing reasonable expectations for patients regarding their visual outcomes after the lens surgery.

UNASSIGNED: Acromelic dysplasia caused by FBN1 mutation includes acromicric dysplasia (AD), geleophysic dysplasia 2 (GD2), and Weill-Marchesani syndrome 2 (WMS2). All three diseases share severe short stature and brachydactyly. Besides phenotypic similarity, there is a molecular genetic overlap among them, as identical FBN1 gene mutations have been identified in patients with AD, GD2, and WMS2. However, no family with different acromelic dysplasia phenotypes due to the same variant has been described in English reports.
UNASSIGNED: The proband presented with typical facial features, severe short stature, short limbs, stubby hands and feet and radiological abnormalities. Her elder sister and mother had similar physical features. In addition, her elder sister was found to have aortic valve stenosis by echocardiography. Mutation analysis demonstrated a heterozygous missense mutation, c.5179C>T (p.Arg1727Trp) in exon 42 of the FBN1. The proband and her mother were diagnosed with AD, and her elder sister with GD2. The proband was treated with recombinant human growth hormone (rhGH) and had a body length gain of 0.72 SDS in half a year.
UNASSIGNED: These findings expand the phenotypic spectrum of FBN1 gene mutations and highlight that identical FBN1 genotypes can result in different phenotypes of acromelic dysplasia in a family. The efficacy of rhGH therapy in patients with acromelic dysplasia is controversial. More follow-up is needed on the long-term efficacy of rhGH therapy.

UNASSIGNED: Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 ( (FBN1). In addition to typical phenotypes such as ectopia lentis (EL) and aortic dilation, patients with MFS are prone to ocular posterior segment abnormalities, including retinal detachment (RD), maculopathy, and posterior staphyloma (PS). This study aims to investigate the correlations between FBN1 genotype and posterior segment abnormalities within a Chinese cohort of MFS.
UNASSIGNED: Retrospective study.
UNASSIGNED: One hundred twenty-one eyes of 121 patients with confirmed FBN1 mutations between January 2015 and May 2023 were included.
UNASSIGNED: Comprehensive ophthalmic examination findings were reviewed, and the incidence of RD, atrophic, tractional, and neovascular maculopathy (ATN classification system), and PS was analyzed between different genotype groups. Only the more severely affected eye from each patient was included.
UNASSIGNED: Clinical features and risk factors.
UNASSIGNED: Of 121 patients, 60 eyes (49.59%) exhibited posterior segment abnormalities, including RD (4, 3.31%), maculopathy (47, 38.84%), and PS (54, 44.63%). The mean age was 11.53 ± 11.66 years, with 79.34% of patients <20 years old. The location and region of mutations were found to be associated with the incidence of maculopathy (P = 0.013, P = 0.033) and PS (P = 0.043, P = 0.036). Mutations in the middle region had a lower incidence of maculopathy and PS (P = 0.028 and P = 0.006, respectively) than those in C-terminal region. Mutations in the transforming growth factor-β (TGF-β) regulating sequence exhibited a higher incidence of maculopathy and PS (P = 0.020, P = 0.040). Importantly, the location and region of mutations were also associated with the incidence of atrophic maculopathy (P = 0.013 and P = 0.033, respectively). Mutations in the middle region had a significantly lower probability of atrophic maculopathy (P = 0.006), while mutations in the TGF-β regulating region had a higher incidence of atrophic maculopathy (P = 0.020).
UNASSIGNED: Maculopathy and PS were associated with the location and region of FBN1 mutations. Patients with mutations in the TGF-β regulating region faced an increased risk of developing retinopathy.
UNASSIGNED: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

UNASSIGNED: Pulmonary alveolar microlithiasis (PAM) is a rare disease whose clinical and imaging manifestations are non-specific, characterized by the deposition of microliths, which primarily consist of calcium and phosphorus, within the alveoli. In the cases of PAM, patients combined with calcification of other organs such as gastric mucosal calcification are less common.
UNASSIGNED: A 59-year-old woman was admitted to our hospital due to cough producing white, foamy sputum, accompanied by dyspnea and fever for 20 days. The CT scan showed diffuse ground-glass opacities and calcification of the gastric mucosa. Lung tissue biopsy revealed the presence of calcification and granulomatous foreign bodies in the interstitium and alveolar cavity. In the later stages, she developed painful skin petechiae. For this patient, the diagnosis of PAM, gastric mucosal calcification, and purpura fulminans was made. However, the genetic test results hinted that the patient and her son had a heterozygous mutation in the FBN1 gene, but her daughter\'s genetic test results were normal. Although the patient received anti-infection treatment, steroids, and oxygen therapy, her condition did not improve.
UNASSIGNED: We reported a rare case of PAM combined with calcification of other organs and purpura fulminans. Treatment of steroids did not show any benefit. The causative mechanism and effective treatment of this disease remain unclear. More treatments need to be explored.

BACKGROUND: Mutations in fibrillin-1 (FBN1) are known to be associated with Marfan syndrome (MFS), an autosomal dominant connective tissue disorder. Most FBN1 mutations are missense or nonsense mutations. Traditional molecular genetic testing for the FBN1 gene, like Sanger sequencing, may miss disease-causing mutations in the gene\'s regulatory regions or non-coding sequences, as well as partial or complete gene deletions and duplications.
METHODS: Next-generation sequencing, multiplex ligation-dependent probe amplification and gap PCR were conducted on two MFS patients to screen for disease-causing mutations.
RESULTS: We identified two large deletions in FBN1 from two MFS patients. One patient had a 0.23 Mb deletion (NC_000015.9:g.48550506_48779360del) including 5\'UTR-exon6 of FBN1. The other patient harbored a 1416 bp deletion (NC_000015.9:g.48410869_48412284del) affecting the last exon, exon 66, of the FBN1 gene.
CONCLUSIONS: Our results expanded the number of large FBN1 deletions and highlighted the importance of screening for large deletions in FBN1 in clinical genetic testing, especially for those with the classic MFS phenotype.

Fibrillin-1 (FBN1) is a large, cysteine-rich, calcium binding extracellular matrix glycoprotein encoded by FBN1 gene. It serves as a structural component of microfibrils and provides force-bearing mechanical support in elastic and nonelastic connective tissue. As such, mutations in the FBN1 gene can cause a wide variety of genetic diseases such as Marfan syndrome, an autosomal dominant disorder characterized by ocular, skeletal and cardiovascular abnormalities. FBN1 also interacts with numerous microfibril-associated proteins, growth factors and cell membrane receptors, thereby mediating a wide range of biological processes such as cell survival, proliferation, migration and differentiation. Dysregulation of FBN1 is involved in the pathogenesis of many human diseases, such as cancers, cardiovascular disorders and kidney diseases. Paradoxically, both depletion and overexpression of FBN1 upregulate the bioavailability and signal transduction of TGF-β via distinct mechanisms in different settings. In this review, we summarize the structure and expression of FBN1 and present our current understanding of the functional role of FBN1 in various human diseases. This knowledge will allow to develop better strategies for therapeutic intervention of FBN1 related diseases.

The objective of this study was to investigate the mechanism of curcumin in diabetic foot ulcer (DFU) wound healing. A DFU rat model was established, and fibroblasts were cultured in a high-glucose (HG) environment to create a cell model. Various techniques, including Western blot, RT‒qPCR, flow cytometry, Transwell, cell scratch test and H&E staining, were employed to measure the levels of relevant genes and proteins, as well as to assess cell proliferation, apoptosis, migration, and pathological changes. The results showed that miR-152-3p was overexpressed in DFU patients, while FBN1 was underexpressed. Curcumin was found to inhibit fibroblast apoptosis, promote proliferation, migration, and angiogenesis in DFU rats, and accelerate wound healing in DFU rats. In addition, overexpression of miR-152-3p weakened the therapeutic effect of curcumin, while overexpression of FBN1 reversed the effects of the miR-152-3p mimic. Further investigations into the underlying mechanisms revealed that curcumin expedited wound healing in DFU rats by restoring the FBN1/TGF-β pathway through the inhibition of miR-152-3p. In conclusion, curcumin can suppress the activity of miR-152-3p, which, in turn, leads to the rejuvenation of the FBN1/TGF-β pathway and accelerates DFU wound healing.

This study used four generations of a Chinese family to reveal the genetic etiology and ocular manifestation pathogenesis of Marfan syndrome (MFS) through whole genome sequencing (WGS) and metabolomics analysis. In the study, we explored the pathogenic gene variant and aqueous humor (AH) metabolites alterations of MFS. Using WGS, a novel heterozygous variant (NM_000138: c.G4192A, p.D1398 N) in the fibrilin-1 (FBN1) gene was identified. This variant was co-segregated with the phenotype and considered \"deleterious\" and highly conserved during evolution. The p.D1398 N variant is located in a cbEGF-like domain and predicted to lead to a new splice site, which might result in structural and functional changes to the FBN1 protein. FBN1 is highly expressed in the mouse cornea, conjunctiva and lens capsule, which highlights the important role of FBN1 in eyeball development. AH metabolomics analysis identified eight differentially expressed metabolites, including 3-hydroxyphenylacetic acid, 4-pyridoxic acid, aminoadipic acid, azelaic acid, chlordiazepoxide, niacinamide, ribose, 1,5-bisphosphate and se-methylselenocysteine, associated with relevant metabolic pathways likely involved in the pathogenesis of ocular symptoms in MFS. Our analysis extends the existing spectrum of disease-causing mutations and reveals metabolites information related to the ophthalmic features of MFS. This may provide a new sight and a basis for the diagnosis and mechanism of MFS.

Previous studies have screened key candidate genes for litter size in sheep, including fibrillin-1 (FBN1), family with sequence similarity 184 member B (FAM184B) and zinc finger and AT-hook domain containing (ZFAT). Therefore, it is necessary to verify these genes in the Xinggao mutton sheep population and determine the associated loci for litter size. In this study, three loci (FBN1 g.160338382 T > C, FAM184B g.398531673 C > T and ZFAT g.20150315 C > T) were firstly screened based on the population differentiation coefficient between the polytocous and monotocous sheep groups. Then, population genetic analysis and association analysis were performed on these loci. The results revealed that the g.160338382 T > C in FBN1 was significantly associated with the litter size of sheep. Moreover, there was no significant interaction effect between the g.160338382 T > C locus and FecB on litter size. Notably, g.160338382 T > C is adjacent to the anterior border of exon 58 and belongs to a splice polypyrimidine tract variant, which may lead to alternative splicing and ultimately cause changes in the structure and function of the protein. In summary, our results provided a potentially effective genetic marker for improving the litter size of sheep.