👤 Udo Bartsch

Tooth agenesis is a common dental anomaly that can substantially affect both the ability to chew and the esthetic appearance of patients. This study aims to identify possible genetic factors that underlie various forms of tooth agenesis and to investigate the possible molecular mechanisms through which human dental pulp stem cells may play a role in this condition. Using whole-exome sequencing of a Han Chinese family with non-syndromic tooth agenesis, a rare mutation in FGFR1 (NM₀₀₁₁₇₄₀₆₃.2: c.103G > A, p.Gly35Arg) was identified as causative and confirmed by Sanger sequencing. Via GeneMatcher, another family with a known variant (NM₀₀₁₁₇₄₀₆₃.2: c.1859G > A, p.Arg620Gln) was identified and diagnosed with tooth agenesis and a rare genetic disorder with considerable intrafamilial variability. Fgfr1 is enriched in the ectoderm during early embryonic development of mice and showed sustained low expression during normal embryonic development of Xenopus laevis frogs. Functional studies of the highly conserved missense variant c.103G > A showed deleterious effects. FGFR1 (c.103G > A) was overexpressed compared to wildtype and promoted proliferation while inhibiting apoptosis in HEK293 and human dental pulp stem cells. Moreover, the c.103G > A variant was found to suppress the epithelial-mesenchymal transition. The variant could downregulate ID4 expression and deactivate the TGF-beta signaling pathway by promoting the expression of SMAD6 and SMAD7. Our research broadens the mutation spectrum associated with tooth agenesis and enhances understanding of the underlying disease mechanisms of this condition. Show less

The neuronal ceroid lipofuscinoses (NCLs) are a group of childhood-onset neurodegenerative lysosomal storage disorders mainly affecting the brain and the retina. In the NCLs, disease-causing mutations in 13 different ceroid lipofuscinoses genes (CLN) have been identified. The clinical symptoms include seizures, progressive neurological decline, deterioration of motor and language skills, and dementia resulting in premature death. In addition, the deterioration and loss of vision caused by progressive retinal degeneration is another major hallmark of NCLs. To date, there is no curative therapy for the treatment of retinal degeneration and vision loss in patients with NCL. In this review, the key findings of different experimental approaches in NCL animal models aimed at attenuating progressive retinal degeneration and the decline in retinal function are discussed. Different approaches, including experimental enzyme replacement therapy, gene therapy, cell-based therapy, and immunomodulation therapy were evaluated and showed encouraging therapeutic benefits. Recent experimental ocular gene therapies in NCL animal models with soluble lysosomal enzyme deficiencies and transmembrane protein deficiencies have shown the strong potential of gene-based approaches to treat retinal dystrophies in NCLs. In CLN3 and CLN6 mouse models, an adeno-associated virus (AAV) vector-mediated delivery of Show less

Juvenile CLN3 disease, the most prevalent form of Batten disease, is a progressive neurodegenerative disorder resulting from mutations in the CLN3 gene. The objective of this study was to design an ophthalmic rating scale for CLN3 disease in order to quantify disease progression. Retrospective, cross-sectional study. Patients underwent ophthalmic evaluations including visual testing, optical coherence tomography and fundus imaging. Patients were also assessed using the Hamburg Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) scoring system. Ophthalmic findings were divided into grades of severity ranging from 0 to 3, and the association between the extent of ocular disease and neurological function and age was assessed. Forty-two eyes of 21 patients were included. The mean age at the time of examination was 13.2 years (range, 5.3-21.9 years). The mean ophthalmic severity grade was 2.4 (range, 0-3). The mean neurological severity score was 9.9 (range, 4-14). Ophthalmic manifestations increased in severity with increasing age of the patients (r = -0.84; P < .001), and a strong correlation was found between the CLN3 ophthalmic rating scale score and the Hamburg JNCL score (r = 0.83; P < .001). Ophthalmic manifestations of CLN3 disease correlate closely with the severity of neurological symptoms and age of the patient. The newly established Hamburg CLN3 ophthalmic rating scale may serve as an objective marker of ocular disease severity and progression and may be valuable tool for the evaluation of novel therapeutic strategies for CLN3 disease. Show less

Effector functions of IgG Abs are regulated by their Fc N-glycosylation pattern. IgG Fc glycans that lack galactose and terminal sialic acid residues correlate with the severity of inflammatory (auto)immune disorders and have also been linked to protection against viral infection and discussed in the context of vaccine-induced protection. In contrast, sialylated IgG Abs have shown immunosuppressive effects. We sought to investigate IgG glycosylation programming during the germinal center (GC) reaction following immunization of mice with a foreign protein antigen and different adjuvants. Mice were analyzed for GC T-cell, B-cell, and plasma cell responses, as well as for antigen-specific serum IgG subclass titers and Fc glycosylation patterns. Different adjuvants induce distinct IgG This study's findings regarding adjuvant-dependent GC responses and IgG glycosylation programming may aid in the development of novel vaccination strategies to induce IgG Abs with both high affinity and defined Fc glycosylation patterns in the GC. Show less

Juvenile CLN3 disease, one of the most common forms of a group of lysosomal storage diseases called neuronal ceroid lipofuscinoses (NCLs), is a progressive neurodegenerative disorder with initial visual deterioration. The objective of this study was to analyse the retinal phenotype of patients with CLN3 disease with the help of recent ophthalmic imaging modalities to distinguish CLN3 disease from other inherited retinal dystrophies. Patients underwent ophthalmic evaluations, including anterior and posterior segment examinations, optical coherence tomography, fundus autofluorescence, near infrared imaging and fundus photography. Patients were also assessed according to the Hamburg juvenile NCL (JNCL) score. Each ophthalmic finding was assessed by three independent examiners and assigned to a clinical severity score. 22 eyes of 11 patients were included. The mean age at examination was 14.4 years (range 11.8-26.4 years), with an average age at initial diagnosis of 8 years (range 4.5-11 years). The mean Hamburg JNCL score was 7.3 (range 0-13). All patients showed a specific macular striation pattern on optical coherence tomography that was independent of age and progression of the disease. Other previously described retinal features of CLN3 disease were classified into four severity grades. This study represents the first prospective observational case series documenting retinal abnormalities in CLN3 disease with the aid of the spectral domain optical coherence tomography. The major finding was a characteristic, striated macular pattern in all patients studied. Particularly in early disease cases, macular striae can potentially help to discriminate CLN3 disease from other inherited forms of retinitis pigmentosa. Show less