Citations

Craniosynostosis is a congenital disorder characterized by premature fusion of cranial sutures. Lambdoid synostosis is a rare and severe form of the disease, but its developmental etiology remains poorly understood. Although ectopic cartilage has been associated with lambdoid suture fusion, whether abnormal chondrocyte development is causative has not been directly tested. Here, we investigated the role of platelet-derived growth factor receptor alpha (PDGFRα) signaling in chondrocyte development and lambdoid suture morphogenesis. Mesoderm-specific expression of an autoactivated Pdgfra allele (Pdgfra+/K) caused premature fusion of the lambdoid and occipitointerparietal sutures, preceded by excessive cartilage expansion during embryogenesis. Spatial transcriptomic analysis identified a PDGFRα-dependent transcriptional program characterized by increased Col2a1, Sox9, and Sfrp2 expression, indicating maintenance of chondrocytes in a proliferative progenitor state. Consistently, PDGFRα-activated chondrocytes exhibited increased proliferation. Moreover, expression of Pdgfra+/K in the Col2a1Cre lineage selectively induced occipitointerparietal suture fusion. Together, these findings demonstrate that PDGFRα signaling promotes proliferative cartilage and impairs chondrocyte maturation, identifying dysregulated chondrogenesis as a developmental mechanism underlying lambdoid craniosynostosis.

AbstractGenome-wide association and candidate gene studies implicate different genetic variants within the 6p21 chromosomal region with different non-Hodgkin lymphoma (NHL) subtypes. Complementing these efforts, we conducted human leukocyte antigen (HLA) class I and class II genotyping among 610 NHL cases and 555 controls of non-Hispanic white descent from a US multicenter study. Allele-disease associations were assessed by logistic regression for NHL and its subtypes. Statistically significant associations between HLA and NHL subtypes include HLA-DRB1*0101 for follicular lymphoma (odds ratio [OR] = 2.14, P < .001), HLA-DRB1*0401 for diffuse large B-cell lymphoma (DLBCL; OR = 0.45, P = .006), and HLA-DRB1*13 and follicular lymphoma (OR = 0.48, P = .008). We further observed significant heterozygote advantage for HLA class I alleles and NHL, and particularly DLBCL (P trend = .01 for elevated risk with increasing number of homozygous alleles). Our results support a role for HLA in the etiology of NHL and its subtypes.