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Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish
Victoria Patterson1,2, Farid Ullah3, Laura Bryant4
1Princeton University, Princeton, NJ 08544, USA.
Abstract:
We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences.
Insights
Rare variants in mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) cause neurodevelopmental differences and congenital anomalies. MAP4K4 regulates embryonic development by restraining RAS signaling.
Area of Science:
- Genetics
- Developmental Biology
- Molecular Signaling
Background:
- Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is involved in crucial cellular signaling pathways.
- MAP4K4 is being explored as a potential therapeutic target for various diseases.
- Genetic variations in MAP4K4 have not been extensively linked to syndromic neurodevelopmental disorders.
Purpose of the Study:
- To investigate the role of MAP4K4 variants in individuals with neurodevelopmental differences and congenital anomalies.
- To elucidate the functional impact of identified MAP4K4 variants using model organisms.
- To establish MAP4K4 as a potential genetic cause for syndromic neurodevelopmental disorders.
Main Methods:
- Analysis of rare variants in MAP4K4 in 21 families with neurodevelopmental differences and congenital anomalies.
- Utilizing zebrafish models to study the function of human MAP4K4 variants.
- Assessing the impact of reduced Map4k4 activity on embryonic development and RAS signaling.
Main Results:
- Identified rare variants in MAP4K4 associated with syndromic neurodevelopmental differences and multiple congenital anomalies.
- Demonstrated that human MAP4K4 variants act as loss-of-function or dominant-negative alleles.
- Showed that decreased Map4k4 activity leads to developmental defects in zebrafish embryos.
- Confirmed MAP4K4's role in restraining hyperactive RAS signaling during early embryogenesis.
Conclusions:
- MAP4K4 negatively regulates RAS signaling in early embryonic development.
- Variants in MAP4K4 identified in affected individuals impair its function.
- MAP4K4 is established as a causal gene for syndromic neurodevelopmental differences.
