MAPK8IP3 Genetic Mutation
MAPK8IP3-Related Neurodevelopmental Disorder
neurodevelopmental disorder with or without variable brain abnormalities (NEDBA) General Discussion
MAPK8IP3-related neurodevelopmental disorder is a rare genetic condition caused by harmful changes (pathogenic variants) in the MAPK8IP3 gene, leading to neurodevelopmental disease. There is a spectrum of severity ranging from mild developmental delays to intellectual disability and physical impairments. Treatment of affected individuals is typically symptom-driven and supportive, focusing on speech, physical and social development.
Signs and Symptoms
Individuals with MAPK8IP3-related disorder have a spectrum of neurodevelopmental disabilities. All affected individuals experience some level of global developmental delay including problems with muscle tone (both hypertonia and hypotonia have been reported) and walking, impaired intellectual development, and poor or absent speech. Some individuals have brain abnormalities visible on MRI including thin corpus callosum, cerebral atrophy, perisylvian polymicrogyria and delayed myelination. EEG abnormalities, including slow waves with spikes, have been reported. Other reported features include:
- Early puberty
- Short stature
- Different facial features(round face, thin upper lip, and/or prominent nasal bridge) ● Curved spine (scoliosis)
- Cortical visual impairment
MAPK8IP3-related neurodevelopmental disorder is caused by harmful changes (pathogenic variants) in the MAPK8IP3 gene. To date, almost all cases have been due de novo gene changes that were not inherited. There have been rare patients with two types of egg or sperm cells (gonadal mosaicism) with and without the genetic variant in MAPK8IP3 in one parent. Both missense and truncating variants in the MAPK8IP3 gene have been reported. Specific symptoms have not yet been associated with particular gene variants. (No clear phenotype-genotype correlation).
Defective transport of cargo along the axons of neurons underlies a variety of rare genetic neurodevelopmental disorders. MAPK8IP3 (mitogen-activated protein kinase 8 interacting protein 3) is highly expressed in brain cells and encodes for the JIP3 protein (JNK-interacting protein 3) which functions as a scaffold/adapter protein that links cargos to the dynein and kinesin motors. JIP3 is important for multiple cellular processes in the developing brain, including axon guidance and the development of the brain (thalamus, hippocampus and cortical plate).
The number of individuals with MAPK8IP3-related disorder is unknown, due to the newly described nature of this condition and variable access to genetic testing. To date, there are 18 affected individuals in the published literature.
KIF1A-related disorder is another rare neurodegenerative disorder that affects motor proteins involved in the transport of vesicles and organelles. Pathogenic variants in the KIF1A gene cause neurological disorders and disabilities ranging from mild to life threatening. Symptoms include intellectual disability, developmental delay, seizures, hypotonia and hypertonia. The treatment for KIF1A-Related Disorder is directed at the specific symptoms that each patient develops. (For more information on this condition, search for KIF1A in the Rare Disease Database.)
Occupational, physical, speech and feeding therapies may be utilized to address specific developmental delays.
Genetic counseling is recommended for affected individuals and their families. Investigational Therapies
Research into the natural history, cellular mechanisms and potential treatment of MAPK8IP3-related disorder is ongoing. Please visit www.wolvfdn.com if you are interested in participating in research or if you are a provider looking to refer a patient to the current MAPK8IP3 natural history study.
Iwasawa S, Yanagi K, Kikuchi A, et al. Recurrent de novo MAPK8IP3 variants cause neurological phenotypes. Ann. Neurol. 2019;85: 927-933.
Platzer K, Sticht H, Edwards SL, et al. De novo variants in MAPK8IP3 cause intellectual disability with variable brain anomalies. Am. J. Hum. Genet. 2019;104: 203-212.
Kelkar N, Gupta S, Dickens M, Davis RJ. Interaction of a mitogen-activated protein kinase signaling module with the neuronal protein JIP3. Molec. Cell. Biol. 2000;20: 1030-1043.
Ito M, Yoshioka K, Akechi M, et al. SAP1, a novel Jun N-terminal protein kinase (JNK)-binding protein that functions as a scaffold factor in the JNK signaling pathway. Molec. Cell. Biol. 1999;19: 7539-7548.
The Wolverine Foundation gratefully acknowledges Wendy Chung, MD, PhD, Clinical and Molecular Geneticist, Kennedy Family Professor of Pediatrics and Medicine, Columbia University Medical Center and Alexa Geltzeiler, ScM, CGC, Department of Pediatrics, Columbia University Medical Center, for the preparation of this report.
Kenneth G. Miller
JSAP1, a Novel Jun N-Terminal Protein Kinase (JNK)-Binding Protein That Functions as a Scaffold Factor in the JNK Signaling Pathway
Nyaya Kelkar, Shashi Gupta, Martin Dickens, and Roger J. Davis
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