🧬 biology

A novel gain of function variant in NUAK2 causes oculomotor apraxia in a three-generation family

This study identifies a novel heterozygous gain-of-function missense variant in the NUAK2 gene as the cause of autosomal dominant congenital oculomotor apraxia and cerebellar vermis hypoplasia in a three-generation family, expanding the gene's known pathogenic mechanisms beyond previously reported loss-of-function variants.

Original authors: Manjekah Dunn, Janine Smith, Christopher R Horne, Meredith Wilson, Elizabeth Emma Palmer, Samuel N Young, Rocio Rius, John W Scott, Ellenore M Martin, Ryan Pysar, Sarah Casauria, Molly Carr, Cassandra

Published 2026-07-09

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Original authors: Manjekah Dunn, Janine Smith, Christopher R Horne, Meredith Wilson, Elizabeth Emma Palmer, Samuel N Young, Rocio Rius, John W Scott, Ellenore M Martin, Ryan Pysar, Sarah Casauria, Molly Carr, Cassandra Gray, Laura Wedd, James M Murphy, John Christodoulou, UDN-Aus Consortium

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ⚕️ This is an AI-generated explanation of a preprint that has not been peer-reviewed. It is not medical advice. Do not make health decisions based on this content. Read full disclaimer

The Big Picture: A Family Mystery Solved

Imagine a family where three generations (a grandmother, her son, and her grandson) all share a specific, unusual trait: they have trouble moving their eyes quickly from side to side. In medical terms, this is called oculomotor apraxia (OMA). It's like their eyes are "stuck" and they have to turn their whole head to look at something new, rather than just darting their eyes.

Doctors also noticed that in all three of these family members, a specific part of the brain called the cerebellar vermis (which helps with balance and coordination) was smaller than usual. While the grandmother had milder symptoms, the father and son also had learning differences, autism, and knee issues.

For a long time, doctors couldn't figure out why this was happening. They checked the family's DNA, but the usual suspects didn't match. This paper is the story of how researchers finally found the culprit.

The Culprit: A Tiny Glitch in the "Engine"

The researchers found a tiny change in a gene called NUAK2. Think of the NUAK2 gene as a blueprint for building a very specific machine inside your cells called a kinase.

To use an analogy:

The Kinase is like a spark plug in a car engine. Its job is to fire at the right time to keep the engine running smoothly.
The Gene is the instruction manual for making that spark plug.

Usually, when people have problems with this gene, the spark plug is broken or missing. It doesn't fire at all (this is called "loss of function"). We already knew that broken spark plugs could cause serious brain development issues, like a baby's brain failing to close properly (anencephaly).

The Twist: The Engine is Revving Too High

In this specific family, the researchers found something different. They didn't find a broken spark plug; they found a spark plug that was stuck in the "on" position.

The specific change in the DNA (a tiny typo called p.Gln168His) didn't stop the machine from working. Instead, it made the machine work twice as fast as it should.

Normal Spark Plug: Fires at a steady, controlled rhythm.
This Family's Spark Plug: Fires frantically and aggressively.

The researchers tested this in a lab. They built the protein with the mutation and watched it work. It was indeed "revving" with nearly double the energy of a normal protein. This is called a "gain of function"—the machine isn't broken; it's too powerful.

Why Does This Matter?

This discovery is a bit like finding out that a car crash wasn't caused by a flat tire (the usual problem), but by someone stepping on the gas pedal too hard.

It explains the family's condition: The paper suggests that having this "super-charged" spark plug disrupts the brain's development, specifically affecting the area that controls eye movements and balance.
It changes the rules: Before this, scientists thought NUAK2 only caused problems when it was broken. Now, we know that if it works too well, it can also cause distinct brain differences.
It's a rare find: This specific "super-charged" version was found in this family and is extremely rare in the general population.

The Conclusion

The researchers concluded that this family's eye movement issues and brain structure differences are caused by this specific "over-active" version of the NUAK2 gene. It's a unique case where the problem isn't that a part is missing, but that a part is working overtime.

This helps doctors understand that for some neurological conditions, the solution isn't just about fixing broken parts, but also understanding what happens when parts work too hard. However, the paper stops there: it identifies the cause but notes that more studies are needed to fully understand how this "over-active" gene leads to these specific symptoms.

Technical Summary: A Novel Gain-of-Function Variant in NUAK2 Causes Oculomotor Apraxia

Problem Statement
Oculomotor apraxia (OMA), specifically the congenital "Cogan type," is characterized by impaired voluntary initiation of rapid horizontal eye movements. It frequently presents with structural brain anomalies, such as cerebellar vermis hypoplasia, and neurodevelopmental comorbidities like autism spectrum disorder (ASD) and developmental delay. Despite the identification of pathogenic variants in numerous genes associated with ataxia, Joubert syndrome, and other metabolic disorders, a significant proportion of congenital OMA cases remain genetically undiagnosed. While NUAK2 (encoding the SNARK kinase) has previously been linked to neurodevelopmental defects via loss-of-function (LoF) mechanisms—such as neural tube defects and anencephaly—the potential for gain-of-function (GoF) variants in NUAK2 to cause distinct neurological phenotypes remained uncharacterized.

Methodology
The study utilized a multi-disciplinary approach combining clinical phenotyping, genomic re-analysis, and functional biochemistry:

Cohort: A three-generation family (proband, father, and paternal grandmother) was recruited through the Australian Undiagnosed Diseases Network (UDN-Aus). All affected members presented with non-progressive OMA and cerebellar vermis hypoplasia confirmed via MRI.
Genomic Analysis: The team performed re-analysis of existing exome sequencing data and conducted genome sequencing (GS) on three affected individuals (I.1, II.2, and III.1). Data processing followed DRAGEN GATK best practices, including joint calling of SNVs and indels, structural variant calling, and mitochondrial variant analysis. Variants were filtered against population databases (gnomAD v4.1) and in silico prediction tools.
Functional Characterization: To determine the molecular mechanism of the identified variant, the researchers synthesized wild-type (WT) and mutant (p.Gln168His) full-length human NUAK2 cDNA. These constructs were expressed in HEK293T cells, purified via FLAG-tag affinity chromatography, and subjected to radiometric kinase assays. Kinase activity was measured by the transfer of radiolabeled phosphate to a synthetic peptide substrate (AMARAtide), quantified via scintillation counting.

Key Results

Genetic Identification: Re-analysis and GS confirmed a heterozygous missense variant in NUAK2 (NM_030952.3:c.504G>C, p.Gln168His) segregating perfectly with the phenotype across all three generations. The variant is extremely rare in the general population (0.0001% frequency in gnomAD) and located in the C-lobe of the kinase domain, adjacent to the activation loop.
Clinical Phenotype: The family exhibited a consistent core phenotype of non-progressive OMA and cerebellar vermis hypoplasia. Variable expressivity was noted: the proband (8 years) and father (33 years) presented with ASD and developmental delay, while the grandmother (69 years) had milder symptoms with no neurodevelopmental deficits but shared the ocular and cerebellar findings. Patellofemoral dysplasia was also observed in affected members.
Functional Mechanism (Gain-of-Function): Contrary to previously reported NUAK2 variants associated with LoF (e.g., p.Val163Met), the p.Gln168His variant demonstrated a gain-of-function mechanism. Radiometric assays revealed that the mutant kinase exhibited a statistically significant, nearly two-fold elevation in catalytic activity compared to the wild-type protein.
Structural Context: The variant resides at the C-terminal end of the $\alpha$ E helix. The authors propose that the substitution of a solvent-exposed glutamine with a bulky, positively charged histidine may alter the positioning of the activation and catalytic loops, promoting a transition to an active-like conformation and elevating basal kinase activity.

Significance and Claims
This study provides the first report implicating a NUAK2 gain-of-function variant in the etiology of oculomotor apraxia and cerebellar vermis hypoplasia. The findings establish that NUAK2 kinase activity must be tightly regulated within a specific range for normal neurodevelopment; both diminished activity (associated with neural tube defects) and elevated activity (associated with OMA) can result in distinct pathological outcomes. The authors conclude that while the p.Gln168His variant explains the phenotype in this specific family, further studies and the identification of additional patients are required to fully clarify the role of NUAK2 hyperactivity in cerebellar development and the broader spectrum of oculomotor apraxia.

The Big Picture: A Family Mystery Solved

The Culprit: A Tiny Glitch in the "Engine"

The Twist: The Engine is Revving Too High

Why Does This Matter?

The Conclusion

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