Phenotypic, molecular, functional, and structural aspects of novel DCX and LIS1 mutations causing the subcortical band heterotopia/lissencephaly (SBH/LIS) spectrum (P2.227)
Bibliographic record
Abstract
OBJECTIVE: To analyse novel DCX and LIS1 mutations employing phenotypic, molecular and functional/structural techniques. BACKGROUND: Most patients with (SBH/LIS) spectrum have either DCX or LIS1 mutations, associated with predominantly anterior or posterior distribution of the malformation, respectively. DESIGN/METHODS: Detailed review of the phenotype of two patients with SBH/LIS spectrum caused by novel mutations in DCX and LIS1; functional analysis of DCX mutation using in vitro fluorescence-based assays with dynamic microtubules; bioinformatic analysis of the LIS1 mutation and mapping on to a structural model of the mutated LIS1 protein. RESULTS: Patient 1 (Pt1) is a 46-year-old woman of French-Canadian ancestry; Patient 2 (Pt2) is a 28-year-old man of British ancestry. Both patients presented with developmental delay and refractory epilepsy, at 3 and 6 months respectively. Brain MRI in Pt1: double cortex predominating in the frontal regions; in Pt2: predominantly posterior lissencephaly associated with partial callosal agenesis, cavum septum pellucidum, and diffuse cerebellar atrophy. Parents declined genetic testing. DCX sequencing in Pt1 showed a c.578delA variant. LIS1 sequencing in Pt2 revealed duplication of five nucleotides in exon 8 (c.728_732dupATCAA). The recombinant mutated DCX protein was found to be defective in promoting microtubule nucleation and polymerization, and showed impaired cooperative binding to microtubules. The change in the mutated LIS1 protein introduces a five residue stretch of altered sequence followed by a premature stop codon at residue 250, early in the 4th WD repeat of the LIS1 beta propeller. CONCLUSIONS: We report two novel pathogenic variants causing severe phenotypes of the SBH/LIS spectrum. Our functional analyses show that the DCX variant disrupts microtubule binding as well as the cooperative interaction between DCX molecules. Our structural interpretation of the LIS1 variant suggests that the LIS1 protein does not fold properly, is unable to bind dynein, and is likely targeted for degradation in cells.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".