POLM variant G312R promotes ovarian tumorigenesis through genomic instability and COL11A1-NF-κB axis.

In ovarian cancer (OC), identifying key molecular players in disease escalation and chemoresistance remains critical. Our investigation elucidates the role of the DNA polymerase mu (POLM), especially G312R mutation, in propelling oncogenesis through dual pathways. POLMG312R markedly augments the ribonucleotide insertion capability of POLM, precipitating genomic instability. In addition, our research reveals that POLMG312R perturbs collagen alpha-1 (XI) chain (COL11A1) expression-a gene that plays a key role in oncogenesis-and modulates the NF-κB signaling pathway, alters the secretion of downstream inflammatory cytokines, and promotes tumor-macrophage interactions. We illustrate a bidirectional regulatory interaction between POLM, particularly its G312R variant, and COL11A1. This interaction regulates NF-κB signaling, culminating in heightened malignancy and resistance to chemotherapy in OC cells. These insights position the POLM as a potential molecular target for OC therapy, shedding light on the intricate pathways underpinning POLM variant disease progression.NEW & NOTEWORTHY Our research reveals that POLM plays an important role in ovarian cancer development, especially the mutation G312R. We uncover the POLMG312R mutation as a driver of genomic instability in ovarian cancer via aberrant ribonucleotide incorporation. We reveal that POLMG312R upregulates COL11A1 and activates NF-κB signaling, contributing to tumor progression and chemoresistance. This study identifies the POLM-COL11A1-NF-κB axis as a novel oncogenic pathway.

[Prenatal phenotype and genetic analysis of a fetus with Fibrochondrogenesis 1 due to compound heterozygous variants of COL11A1 gene].

OBJECTIVE: To explore the genetic etiology of a fetus with short limbs identified by prenatal ultrasonography. METHODS: A fetus detected with short limb malformations at Shengjing Hospital Affiliated to China Medical University on October 25, 2021 was selected as the study subject. Prenatal ultrasound and post-abortion imaging were carried out to determine the phenotypic characteristics of the fetus. Amniotic fluid sample of the fetus and peripheral blood samples of its parents were collected. Following extraction of genomic DNA, whole-exome sequencing was carried out. Candidate variants were verified by Sanger sequencing. Online software was used to predict the structural changes of the mutant proteins. RESULTS: Prenatal ultrasound showed that the fetus had a small bell-shaped thorax, markedly shortened limbs, flat midface, a small nose with anteriorly tilted nostrils, and a small mandible. Post-abortion CT showed typical short and wide fetal ribs, cupped metaphyses at both ends, short long bones with wide metaphyses, resulting in a dumbbell-shaped appearance and curved thoracic vertebrae. Whole-exome sequencing revealed that the fetus had harbored compound heterozygous variants of the COL11A1 gene, namely c.2251G>T and c.3790G>T, both of which were predicted to alter the important Gly-X-Y structure of collagen protein. Sanger sequencing confirmed that the variants were respectively inherited from its parents. CONCLUSION: A rare fetus with Fibrochondrogenesis type 1 due to compound heterozygous variants of the COL11A1 gene has been diagnosed. Above finding has enabled genetic counseling and reproductive guidance for this family.

Association of genetic variation in COL11A1 with adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a common and progressive spinal deformity in children that exhibits striking sexual dimorphism, with girls at more than fivefold greater risk of severe disease compared to boys. Despite its medical impact, the molecular mechanisms that drive AIS are largely unknown. We previously defined a female-specific AIS genetic risk locus in an enhancer near the PAX1 gene. Here, we sought to define the roles of PAX1 and newly identified AIS-associated genes in the developmental mechanism of AIS. In a genetic study of 10,519 individuals with AIS and 93,238 unaffected controls, significant association was identified with a variant in COL11A1 encoding collagen (α1) XI (rs3753841; NM_080629.2_c.4004C>T; p.(Pro1335Leu); p=7.07E-11, OR = 1.118). Using CRISPR mutagenesis we generated Pax1 knockout mice (Pax1-/-). In postnatal spines we found that PAX1 and collagen (α1) XI protein both localize within the intervertebral disc-vertebral junction region encompassing the growth plate, with less collagen (α1) XI detected in Pax1-/- spines compared to wild-type. By genetic targeting we found that wild-type Col11a1 expression in costal chondrocytes suppresses expression of Pax1 and of Mmp3, encoding the matrix metalloproteinase 3 enzyme implicated in matrix remodeling. However, the latter suppression was abrogated in the presence of the AIS-associated COL11A1P1335L mutant. Further, we found that either knockdown of the estrogen receptor gene Esr2 or tamoxifen treatment significantly altered Col11a1 and Mmp3 expression in chondrocytes. We propose a new molecular model of AIS pathogenesis wherein genetic variation and estrogen signaling increase disease susceptibility by altering a PAX1-COL11a1-MMP3 signaling axis in spinal chondrocytes.

Adolescent idiopathic scoliosis (AIS) is a twisting deformity of the spine that occurs during periods of rapid growth in children worldwide. Children with severe cases of AIS require surgery to stop it from getting worse, presenting a significant financial burden to health systems and families. Although AIS is known to cluster in families, its genetic causes and its inheritance pattern have remained elusive. Additionally, AIS is known to be more prevalent in females, a bias that has not been explained. Advances in techniques to study the genetics underlying diseases have revealed that certain variations that increase the risk of AIS affect cartilage and connective tissue. In humans, one such variation is near a gene called Pax1, and it is female-specific. The extracellular matrix is a network of proteins and other molecules in the space between cells that help connect tissues together, and it is particularly important in cartilage and other connective tissues. One of the main components of the extracellular matrix is collagen. Yu, Kanshour, Ushiki et al. hypothesized that changes in the extracellular matrix could affect the cartilage and connective tissues of the spine, leading to AIS. To show this, the scientists screened over 100,000 individuals and found that AIS is associated with variants in two genes coding for extracellular matrix proteins. One of these variants was found in a gene called Col11a1, which codes for one of the proteins that makes up collagen. To understand the relationship between Pax1 and Col11a1, Yu, Kanshour, Ushiki et al. genetically modified mice so that they would lack the Pax1 gene. In these mice, the activation of Col11a1 was reduced in the mouse spine. They also found that the form of Col11a1 associated with AIS could not suppress the activation of a gene called Mmp3 in mouse cartilage cells as effectively as unmutated Col11a1. Going one step further, the researchers found that lowering the levels of an estrogen receptor altered the activation patterns of Pax1, Col11a1, and Mmp3 in mouse cartilage cells. These findings suggest a possible mechanism for AIS, particularly in females. The findings of Yu, Kanshour, Ushiki et al. highlight that cartilage cells in the spine are particularly relevant in AIS. The results also point to specific molecules within the extracellular matrix as important for maintaining proper alignment in the spine when children are growing rapidly. This information may guide future therapies aimed at maintaining healthy spinal cells in adolescent children, particularly girls.

Analysis of cancer-associated fibroblasts related genes identifies COL11A1 associated with lung adenocarcinoma prognosis.

BACKGROUND: The treatment of lung adenocarcinoma is difficult due to the limited therapeutic options. Cancer-associated fibroblasts play an important role in the development of cancers. This study aimed to identify a promising molecular target associated with cancer-associated fibroblasts for the treatment of lung adenocarcinoma. METHODS: The Cancer Genome Atlas lung adenocarcinoma dataset was used to screen hub genes associated with cancer-associated fibroblasts via the EPIC algorithm and Weighted Gene Co-expression Network Analysis. Multiple databases were used together with our data to verify the differential expression and survival of COL11A1. Functional enrichment analysis and the single-cell TISCH database were used to elucidate the mechanisms underlying COL11A1 expression. The correlation between COL11A1 and immune checkpoint genes in human cancers was also evaluated. RESULTS: Using the EPIC algorithm and Weighted Gene Co-expression Network Analysis, 13 hub genes associated with cancer-associated fibroblasts in lung adenocarcinoma were screened. Using the GEPIA database, Kaplan-Meier Plotter database, GSE72094, GSE75037, GSE32863, and our immunohistochemistry experiment data, we confirmed that COL11A1 overexpresses in lung adenocarcinoma and that high expression of COL11A1 is associated with a poor prognosis. COL11A1 has a genetic alteration frequency of 22% in patients with lung adenocarcinoma. COL11A1 is involved in the extracellular matrix activities of lung adenocarcinoma. Using the TISCH database, we found that COL11A1 is mainly expressed by cancer-associated fibroblasts in the tumor microenvironment rather than by lung adenocarcinoma cells. Finally, we found that COL11A1 is positively correlated with HAVCR2(TIM3), CD274 (PD-L1), CTLA4, and LAG3 in lung adenocarcinoma. CONCLUSION: COL11A1 may be expressed and secreted by cancer-associated fibroblasts, and a high expression of COL11A1 may result in T cell exhaustion in the tumor microenvironment of lung adenocarcinoma. COL11A1 may serve as an attractive biomarker to provide new insights into cancer therapeutics.

Microphthalmia and congenital cataract in two patients with Stickler syndrome type II: a case report.

BACKGROUND: Stickler syndrome (STL) is a collagenopathy caused by pathogenic variants in collagen-coding genes, mainly COL2A1 or COL11A1 associated with Stickler syndrome type 1 (STL1) or type 2 (STL2), respectively. Affected individuals manifest ocular, auditory, articular, and craniofacial findings in varying degrees. Previous literature and case reports describe high variability in clinical findings for patients with STL. With this case report, we broaden the clinical spectrum of the phenotype. MATERIALS AND METHODS: Case report on two members of a family (mother and son) including clinical examination and genetic testing using targeted trio whole exome sequencing (trio-WES). RESULTS: A boy and his mother presented with microphthalmia, congenital cataract, ptosis, and moderate-to-severe sensorineural hearing loss. Trio-WES found a novel heterozygote missense variant, c.4526A>G; p(Gln1509Arg) in COL11A1 in both affected individuals. CONCLUSIONS: We report a previously undescribed phenotype associated with a COL11A1-variant in a mother and son, expanding the spectrum for phenotype-genotype correlation in STL2, presenting with microphthalmia, congenital cataract, and ptosis not normally associated with Stickler syndrome.

Multiocular defect in the Old English Sheepdog: A canine form of Stickler syndrome type II associated with a missense variant in the collagen-type gene COL11A1.

Multiocular defect has been described in different canine breeds, including the Old English Sheepdog. Affected dogs typically present with multiple and various ocular abnormalities. We carried out whole genome sequencing on an Old English Sheepdog that had been diagnosed with hereditary cataracts at the age of five and then referred to a board-certified veterinary ophthalmologist due to owner-reported visual deterioration. An ophthalmic assessment revealed that there was bilateral vitreal degeneration, macrophthalmos, and spherophakia in addition to cataracts. Follow-up consultations revealed cataract progression, retinal detachment, uveitis and secondary glaucoma. Whole genome sequence filtered variants private to the case, shared with another Old English Sheepdog genome and predicted to be deleterious were genotyped in an initial cohort of six Old English Sheepdogs (three affected by multiocular defect and three control dogs without evidence of inherited eye disease). Only one of the twenty-two variants segregated correctly with multiocular defect. The variant is a single nucleotide substitution, located in the collagen-type gene COL11A1, c.1775T>C, that causes an amino acid change, p.Phe1592Ser. Genotyping of an additional 14 Old English Sheepdogs affected by multiocular defect revealed a dominant mode of inheritance with four cases heterozygous for the variant. Further genotyping of hereditary cataract-affected Old English Sheepdogs revealed segregation of the variant in eight out of nine dogs. In humans, variants in the COL11A1 gene are associated with Stickler syndrome type II, also dominantly inherited.