Pandey Lab at UPMC Children’s Receives NIH R01 Grant to Further Studies of GEMIN5-driven Neurodevelopmental Disorder

Congratulations to the Pandey Laboratory and the UPMC Children’s Hospital of Pittsburgh Division of Child Neurology for receiving a National Institutes of Health R01 grant to further their ground-breaking studies of a genetically-driven rare neurological disorder caused by mutations of the GEMIN5 protein that the team was the first to discover several years ago.

Historical Perspective

The Pandey Laboratory, led by Udai Pandey, PhD, professor of Pediatrics and director of the Children’s Neuroscience Institute, along with collaborators from UPMC Children’s, including Deepa S. Rajan, MD, FAAP, associate professor of Pediatrics, director of Neurogenetics and the UPMC Children’s Center for Neurogenomics (CCNG), and collaborators from around the world published a seminal paper in 2021 in Nature Communications about their discovery of the GEMIN5-mediated disorder.

The international team, led by the UPMC Children’s research team and Pandey Lab identified the genetic cause of a rare neurological disorder characterized by developmental delay and loss of coordination, or ataxia.

The disorder is caused by mutations in the GEMIN5 protein. GEMIN5 is one of the key building blocks of a protein complex that controls RNA metabolism in neurons. Prior to the team’s discovery, no mutations in GEMIN5 were previously linked to any genetic disease.

GEMIN5 is part of a protein complex that regulates a number of important cellular processes, including the development of dendrites and axons. Interestingly, mutations in another key protein of the complex, named survival motor neuron protein (SMNP), cause a different devastating disorder — spinal muscular atrophy.

For the study published in 2021, the UPMC Children’s team contacted clinicians around the world, eventually collecting data from 30 patient families in 12 different countries.

Because isolating live neurons from people isn’t possible, the team had to come up with another way of getting samples for future testing. They collected blood samples from pediatric patients who were referred to neurogenetic clinics with undiagnosed neurological symptoms. Blood samples were then processed to isolate cells that, with careful tinkering in the lab, were reprogrammed into neurons.

After comparing genetic material of reprogrammed neurons from sick children with that of unaffected relatives, the research team was able to link neurologic manifestations of the disease to 26 mutations in the GEMIN5 gene that cause damage to the structure of the protein.

Additional experiments they conducted linked damage to the GEMIN5 protein to disease manifestations more definitively. They found that depleting an analog of human neuronal GEMIN5 protein in fruit flies was deadly if it happened in early stages of the fly’s life cycle, or drastically delayed its development if such disruption happened later.

Since these initial studies, the team has continued its research to fully characterize functional aspects of the disorder.

The new NIH R01 grant is aimed exactly at further this task.

R01 Details and Study Aims

In the new R01-funded study (1R01NS134215-01), the Pandey Lab and its collaborators will continue their exploration of GEMIN5-driven cerebellar ataxia syndrome (CAS) functional molecular mechanisms at play in the disorder.

The R01 grant is focused on unraveling the impact of mutations in the GEMIN5 protein linked to neurological issues such as motor dysfunction and cerebellar atrophy. The research aims to conduct a comprehensive analysis of GEMIN5 in neurons, explore the potential mitochondrial malfunctions caused by GEMIN5 variations in cells and live organisms, and scrutinize the effects of these mutations using small animal models.

Initial observations from the team’s prior research have indicated a decrease in the presence and stability of the GEMIN5 protein in specific neurons. This finding suggests a potential deficiency in functionality. Earlier experiments using Drosophila revealed signs of motor issues and a shortened lifespan when its corollary protein to GEMIN5 – the rigor mortis protein – was knocked down. Notably, the team also found in their prior work that CoQ10 enzyme treatment appears to mitigate the severity of symptoms in humans affected by GEMIN5 mutations. This finding could show promising potential for therapeutic approaches with more exploration.

The grant will support further exploration of these topics, aiming to clarify the GEMIN5 mutations’ influence on motor neuron degradation and uncover the affected cellular pathways.

Select Bibliography of Published Research on GEMIN5

For additional reading, below is a selection of the research team’s prior published studies on GEMIN5, including the reference for the 2021 paper in Nature Communications described at the beginning of the article.

• Fortuna TR, Kour S, Chimata AV, Muiños-Bühl A, Anderson EN, Nelson Iv CH, Ward C, Chauhan O, O'Brien C, Rajasundaram D, Rajan DS, Wirth B, Singh A, Pandey UB. SMN regulates GEMIN5 expression and acts as a modifier of GEMIN5-mediated neurodegeneration. Acta Neuropathol. 2023 Sep;146(3):477-498.

   

• Altassan R, Qudair A, Alokaili R, Alhasan K, Faqeih EA, Alhashem A, Alowain M, Alsayed M, Rahbeeni Z, Albadi L, Alkuraya FS, Anderson EN, Rajan D, Pandey UB. Further delineation of GEMIN4 related neurodevelopmental disorder with microcephaly, cataract, and renal abnormalities syndrome. Am J Med Genet A. 2022 Oct;188(10):2932-2940.

   

• Francisco-Velilla R, Embarc-Buh A, Del Caño-Ochoa F, Abellan S, Vilar M, Alvarez S, Fernandez-Jaen A, Kour S, Rajan DS, Pandey UB, Ramón-Maiques S, Martinez-Salas E. Functional and structural deficiencies of Gemin5 variants associated with neurological disorders. Life Sci Alliance. 2022 Apr 7;5(7):e202201403.

   

• Rajan DS, Kour S, Fortuna TR, Cousin MA, Barnett SS, Niu Z, Babovic-Vuksanovic D, Klee EW, Kirmse B, Innes M, Rydning SL, Selmer KK, Vigeland MD, Erichsen AK, Nemeth AH, Millan F, DeVile C, Fawcett K, Legendre A, Sims D, Schnekenberg RP, Burglen L, Mercier S, Bakhtiari S, Francisco-Velilla R, Embarc-Buh A, Martinez-Salas E, Wigby K, Lenberg J, Friedman JR, Kruer MC, Pandey UB. Autosomal Recessive Cerebellar Atrophy and Spastic Ataxia in Patients With Pathogenic Biallelic Variants in GEMIN5. Front Cell Dev Biol. 2022 Feb 28;10:783762.

   

• Kour S, Rajan DS, Fortuna TR, Anderson EN, Ward C, Lee Y, Lee S, Shin YB, Chae JH, Choi M, Siquier K, Cantagrel V, Amiel J, Stolerman ES, Barnett SS, Cousin MA, Castro D, McDonald K, Kirmse B, Nemeth AH, Rajasundaram D, Innes AM, Lynch D, Frosk P, Collins A, Gibbons M, Yang M, Desguerre I, Boddaert N, Gitiaux C, Rydning SL, Selmer KK, Urreizti R, Garcia-Oguiza A, Osorio AN, Verdura E, Pujol A, McCurry HR, Landers JE, Agnihotri S, Andriescu EC, Moody SB, Phornphutkul C, Sacoto MJG, Begtrup A, Houlden H, Kirschner J, Schorling D, Rudnik-Schöneborn S, Strom TM, Leiz S, Juliette K, Richardson R, Yang Y, Zhang Y, Wang M, Wang J, Wang X, Platzer K, Donkervoort S, Bönnemann CG, Wagner M, Issa MY, Elbendary HM, Stanley V, Maroofian R, Gleeson JG, Zaki MS, Senderek J, Pandey UB. Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder. Nat Commun. 2021 May 7;12(1):2558.