Progressive neurological disease with gingival hyperplasia due to TBC1D2B gene deficiency

Background Introduction

In recent years, with the rapid development of genomic technologies, scientists have gained deeper insights into the relationship between genetic variations and human diseases. Increasingly, research has revealed the important role these genetic variations play in neurodevelopment and neurodegenerative diseases. The TBC1D2B gene belongs to the Tre2-Bub2-Cdc16 (TBC) domain-containing Rab-specific GTPase-activating protein (TBC/RabGAPs) family. Previous studies have linked biallelic loss-of-function variants in the TBC1D2B gene to five patients with cognitive impairment and epilepsy, with or without gingival hyperplasia. However, the understanding of the phenotypic spectrum and molecular mechanisms of TBC1D2B gene variants remains incomplete. Therefore, the latest research by Frederike L. Harms et al. aims to further clarify the role of this gene in neurological diseases by reporting five new patients carrying biallelic TBC1D2B variants and detailing the molecular and clinical characteristics of ten known patients to date.

Paper Source

This academic paper was jointly written by multiple scientists including Frederike L. Harms, Jessica Erin Rexach, Stephanie Efthymiou, and others, from institutions such as the University Medical Center Hamburg-Eppendorf in Germany, the University of California Los Angeles in the USA, and UCL Queen Square Institute of Neurology in the UK. The paper was published in the European Journal of Human Genetics in 2024.

Research Process

Research Subjects and Methods

The study collected samples from five newly diagnosed patients (numbered 7 to 11) carrying biallelic TBC1D2B variants, obtained through gene matching or referral mechanisms. The researchers performed genetic sequencing on these patients, analyzed the effects of TBC1D2B variants on transcription and protein levels, and combined data from five previously reported patients to provide a detailed description of the clinical and molecular characteristics of a total of ten patients carrying TBC1D2B variants.

Genetic Analysis

Genomic DNA was extracted from the subjects’ peripheral blood, and trio whole-exome sequencing, whole-genome sequencing, and singleton whole-exome sequencing were performed. TBC1D2B variants were verified and segregated by Sanger sequencing when necessary. TBC1D2B transcript and protein level analyses were conducted on two of the five patients, using quantitative real-time PCR and immunoblotting methods to assess TBC1D2B mRNA and protein levels.

Clinical Data Analysis

Through analyzing the clinical features of ten patients carrying biallelic loss-of-function variants in TBC1D2B, the study found:

1. Development and Cognition: Half of the patients developed normally in childhood, while the other half showed developmental delays. Most patients experienced mental deterioration between 5 and 20 years of age. Language impairment was common, with some patients having no language abilities at all.

2. Gingiva and Mandible: Eight patients developed gingival hyperplasia in early childhood, with some requiring surgical intervention. Eight patients showed abnormal mandibular morphology, some with fibrous dysplasia.

3. Epilepsy and Neurological Abnormalities: Most patients experienced epilepsy, which could be controlled with medication. Neurological abnormalities varied, including cerebral and cerebellar atrophy, enlarged lateral ventricles, and behavioral abnormalities. Some patients developed motor disorders, even requiring long-term bed rest.

4. Vision and Hearing: Half of the patients had varying degrees of vision loss or blindness, with one patient having complex eye abnormalities. Several patients also had bilateral hearing loss.

5. Other Clinical Features: Many patients developed flexion contractures of fingers and toes, and some had low blood cell counts accompanied by hematological disorders.

Data Analysis and Statistics

Quantitative data were statistically analyzed using GraphPad Prism 8 software. One-way ANOVA was used for protein level measurements, followed by Dunnett’s multiple comparisons test (P < 0.05 was considered statistically significant).

Main Research Findings

Molecular Characteristics

The study identified 12 different TBC1D2B variants, including seven nonsense variants, three frameshift variants, one splice site variant, and one missense variant. In fibroblasts from patients with biallelic gene inactivation, TBC1D2B mRNA and protein levels were significantly reduced. In leukocytes from patient 8 with the c.360+1G>T variant, an abnormal TBC1D2B transcript was found, and mRNA levels were significantly reduced.

Clinical Feature Analysis

The study summarized the core phenotypic features of ten patients carrying biallelic TBC1D2B variants, including developmental disorders, epileptic seizures, progressive neurological degeneration, gingival hyperplasia, and mandibular abnormalities. This finding suggests that the syndrome caused by TBC1D2B gene deficiency is a distinct and recognizable genetic syndrome.

Conclusions and Significance

TBC1D2B-related disease is a progressive neurological disorder accompanied by characteristic abnormalities such as gingival hyperplasia and mandibular deformities. The study revealed the important regulatory role of TBC1D2B in autophagy and the intracellular lysosomal system, explaining the possible link between neurological dysfunction and neurodegenerative diseases through this new mechanism.

Research Highlights

1. Expanded Phenotypic Spectrum of TBC1D2B Variants: This study reported five new patients for the first time, greatly expanding the known phenotypic spectrum of TBC1D2B variants.

2. Detailed Molecular and Clinical Characteristics: By combining molecular data and clinical features, this study presented in detail the core characteristics of the syndrome caused by TBC1D2B variants, establishing a clear framework for its disease phenotype.

3. New Insights into Autophagy and Intracellular Lysosomal System: The study emphasized the important role of TBC1D2B in autophagy and the intracellular lysosomal system, proposing that defects in these systems may be potential mechanisms for neurodegenerative diseases, providing new ideas for further research on pathological mechanisms and possible therapeutic strategies.

This study not only greatly deepens the understanding of TBC1D2B gene function and related diseases but also provides an important theoretical basis for exploring possible treatment approaches.