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Recessive Mutation May Cause New Neurodevelopmental Disorder

NEW YORK (GenomeWeb) – Researchers have uncovered a new neurodevelopmental disorder that affects a pair of siblings through exome sequencing and other analyses.

In a new study published this week in eLife, researchers using a combination of sequencing and functional assays uncovered a mutation in the calcium/calmodulin-dependent protein kinase II (CAMK2A) gene. They reported that a pair of siblings who inherited two copies of the mutated gene later showed developmental delays, adding that this is the first Mendelian human disease caused by bialleleic CAMK2A mutations.

"Neuroscientists working to understand childhood brain development, neuronal function, and memory formation also need to consider this new disease, since CAMK2A is associated with these processes," co­first author Franklin Zhong, a research scientist at A*Star, said in a statement. "In [the] future, it would be interesting to test whether restoring CAMK2A activity can bring therapeutic benefit to patients with this condition, as well as those with related neurological disorders."

The affected siblings in this study are from a consanguineous family from Jordan and exhibited global neurodevelopmental delay along with seizures and convulsions. Through identity-by-descent homozygosity mapping using samples from the affected siblings, three healthy siblings, and the unaffected parents, the researchers homed in on a candidate locus on chromosome 5 that covered 28 megabases.

Whole-exome sequencing of one of the affected siblings enabled the researchers to further focus in on four homozygous variants that fell in that region on chromosome 5. After filtering out known minor allele variants, the researchers zeroed in on the missense mutation p.His477Tyr in the CAMK2A gene. Using Sanger sequencing, the researchers found this mutation segregated with disease in all seven affected family members.

CAMK2A, the researchers noted, is neuron-specific and has a key role in synaptic plasticity, learning, and memory. Mice that lack it have decreased spatial memory and reduced long-term potentiation in the hippocampus.

The histidine residue affected by the p.His477Tyr missense mutation is conserved among both vertebrates and invertebrates, the researchers noted. They added that the p.His477Tyr missense mutation, which falls in the CAMK2A association domain,  is predicted to be deleterious by a number of algorithms.

Using dermal fibroblasts from one of the affected siblings, Zhong and his colleagues developed induced pluripotent stem cells, which they then differentiated into neurons. These patient-derived neurons matured just like wild-type ones, but had a reduction in the number of spontaneous spikes and mean firing rate.

In a series of functional assays in cells in culture, the researchers further observed that p.His477Tyr mutant proteins were smaller than wild type and even another type of mutant protein. This suggested to them that the mutation disrupts the ability of the CAMK2A subunits to interact with one another, which is needed for it to act as a holoenzyme.

They additionally reported that there was a reduced abundance of p.His477Tyr mutant proteins, which could be due to decreased protein stability, and that it didn't localize to the proper subcellular regions in neurons, possibly also affecting its ability to function correctly.

As the region is highly conserved, they turned to the model organism Caenorhabditis elegans to test whether p.His477Tyr is the pathogenic allele. In the worms, the researchers found the mutation in the worm homolog of CAMK2A affects both neuronal communication and motor function, and that the addition of the wild-type protein could rescue mutant worms.

Zhong and his colleagues noted that while other studies have implicated single-copy mutations in CAMK2A or CAMK2B in intellectual disability, theirs is the first to find a recessive CAMK2A disorder. They further suggested that mutations in CAMK2A paralogs could also contribute to other neurological disorders.