Biophysical classification of a CACNA1D de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder.
Nadja T Hofer, Petronel Tuluc, Nadine J Ortner and 6 others
PMID 31921405WHAT IT FOUND
A rare CACNA1D variant in twins with severe speech and language delay and autism made calcium channels more active in cells and more sensitive to isradipine.
Another variant at the same position reduced channel activity.
Key findings
01Both thirteen-year-old male monozygotic twins with severe neurodevelopmental disorder, delayed speech and language, and autism carried one copy of a CACNA1D S652L variant absent from a database of 141,456 healthy control genomes.
02In cell recordings, S652L shifted Cav1.3 activation and steady-state inactivation to more negative voltages and increased calcium current during simulated plateau potentials, supporting gain of channel function.
03Isradipine inhibited S652L channels at lower concentrations than normal channels in cells, with half-maximal inhibition reported as 18.1 nM for S652L and 60.3 nM for normal channels, while the S652W variant at the same position shifted gating to more positive voltages and was reported in three healthy people.
STILL TO COME
How it was doneWhat they foundWhat it means for SLPs
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What it does not show
The clinical evidence comes from both twins, who are monozygotic, so it does not show how common this mutation is or how it behaves in unrelated people. The patients also had a KIF22 frameshift variant, although the authors argue it is unlikely to explain the severe neurodevelopmental phenotype. Most results are from mutated channels in kidney cells, not from human neurons, and the paper does not show downstream signalling changes in the brain. Isradipine sensitivity was measured in cells only; no clinical trial tested whether isradipine or other LTCC blockers improve symptoms. The paper does not evaluate speech, occupational, or physical therapy outcomes.
Declared interests
The Austrian Science Fund is named as funder. No other conflict of interest statement is provided in the supplied text.
The easy way to misread this
Do not treat a child's speech or language delay with isradipine because of this paper. The isradipine result came from mutated channels in cells, not from patients, and no clinical trial showed that it improves symptoms.