A novel neurological disorder associated with the Polycomb complex
identified

Date:
July 8, 2021
Source:
Texas Children's Hospital
Summary:
A multi-institutional study has discovered spontaneous mutations in
RNF2 (RING2) gene as the underlying cause of a novel neurological
disorder.



FULL STORY ==========================================================================
A multi-institutional study has discovered spontaneous mutations in
RNF2 (RING2) gene as the underlying cause of a novel neurological
disorder. This Undiagnosed Diseases Network (UDN) study was led by
Dr. Shinya Yamamoto, investigator at the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children's Hospital and assistant
professor at Baylor College of Medicine, and Dr. Vandana Shashi at
Duke University Medical Center. Using a combination of comprehensive
clinical tests, trio genome sequencing and functional studies in
the fruit flies, and global gene matchmaking efforts, the teams found loss-of-function variants in RNF2 gene disrupt normal neuronal development
and function that likely resulted in a wide gamut of symptoms from severe intellectual disabilities, hypotonia, impaired motor skills, epilepsy,
growth retardation, seizures and feeding difficulties in two affected individuals. The study appeared in the journal Human Molecular Genetics.


==========================================================================
The UDN is a National Institutes of Health-funded research study that
brings together clinical and research experts from across the United
States to solve the most challenging medical mysteries using advanced technologies. This often involves severely affected patients who,
despite years of testing, are unable to get a definitive diagnosis
for their medical problems -- the crucial first step towards receiving appropriate treatment, support and clinical care.

This study was initiated with the enrollment of an adolescent female
patient with the above-mentioned symptoms at one of the UDN's Clinical
sites at Duke University. Initially, researchers at Dr. Shashi's lab
at Duke performed a whole slew of genetic tests, all of which came back negative. Next, they performed trio whole-exome sequencing, a relatively
newer sequencing technology that compares the DNA sequences of the parents
and the affected individuals to identify a potential genetic alteration
that might explain these symptoms.

Using this method, they found this patient carried a rare mis-sense
variant in the RNF2 gene, which was not present in genomes of either
parent, indicating that the mutation arose spontaneously in the patient's genome.

RNF2 belongs to a large family of evolutionarily conserved Polycomb
group genes that encode about 20 proteins critical for brain and
skeletal development and function. Mutations in 12 genes that encode
proteins of this complex are known to be associated with neurological disorders. However, RNF2 variants had never been linked to a disease
before. To identify more patients with this new mutation, the team
utilized GeneMatcher, a web tool developed as part of the Baylor-Hopkins
Center for Mendelian Genomics for rare disease researchers. This helped
them find a younger female patient in France who had a different mis-
sense variant in the same gene and suffered from similar symptoms. This
was an exciting finding because it suggested that variations in RNF2
were the likely culprit behind these patients' symptoms and linked RNF2
to a novel neurological disorder. However, to firmly establish a causal relationship between RNF2 variants and the new disease pathology, they
needed to better understand the biological consequence of the variants
found in the two patients, ideally in an in vivo animal model.

The UDN's Model Organisms Screening Core (MOSC) led by Drs. Hugo Bellen,
Shinya Yamamoto and Michael Wangler at the NRI and Baylor carried out
this task by using the fruit fly, Drosophila melanogaster. Fruit flies
are excellent model systems to test the function of variants identified in disease patients, and MOSC researchers have used this strategy to identify
more than 20 new disease gene discoveries in the past few years. When
the MOSC team expressed mutated versions of this gene in fruit flies,
they were unable to functionally rescue i.e., compensate for the loss
of function of this gene, which is in contrast to what they observed
when they expressed the normal version of this gene in flies.

"Using fruit flies as a 'living test tube,' we demonstrated that
loss-of- function mutations in RNF2 were likely the molecular cause of
the symptoms in the two patients," Yamamoto said. "This makes RNF2 the thirteenth Polycomb group gene to be linked to human disease. Although the incidence of each of these dozen diseases that arise from mutations in
Polycomb genes is very rare, it is likely they share similar underlying pathogenic mechanisms. Therefore, we propose the term 'polycombopathies'
to group and study them together." While further studies will be needed
to better define the clinical spectrum and pathologies of this disorder
caused by RNF2, the team is particularly excited by the future therapeutic possibilities that this investigation has opened up.

"Many drugs that modulate the activity of Polycomb group proteins and
their interacting partners are currently being studied in the context
of various cancers and there is mounting evidence pointing towards
convergence in the disease pathologies of cancer and rare neurological
diseases at the molecular level, which will greatly facilitate our goal
to find therapies for 'Polycombopathies," Yamamoto added.

========================================================================== Story Source: Materials provided by Texas_Children's_Hospital. Original
written by Rajalaxmi Natarajan, PhD. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Xi Luo, Kelly Schoch, Sharayu V Jangam, Venkata Hemanjani Bhavana,
Hillary K Graves, Sujay Kansagra, Joan M Jasien, Nicholas Stong,
Boris Keren, Cyril Mignot, Claudia Ravelli, Hugo J Bellen, Michael
F Wangler, Vandana Shashi, Shinya Yamamoto. Rare deleterious
de novo missense variants in Rnf2/Ring2 are associated with a
neurodevelopmental disorder with unique clinical features. Human
Molecular Genetics, 2021; 30 (14): 1283 DOI: 10.1093/hmg/ddab110 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/07/210708135332.htm

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