Nab2/ZC3H14 Protein and Inherited Intellectual Disability

Topic: Cognitive Disabilities
Author: Emory University
Published: 2011/07/05 - Updated: 2022/08/12 - Peer-Reviewed: Yes
Contents: Summary - Definition - Introduction - Main - Related

Synopsis: Mutation in the ZC3H14 gene showed up in two independent family trees affected by intellectual disability. The Berlin/Tehran team studied families in Iran where cousins marry, looking for genetic mutations that lead to intellectual disability. Affected individuals can be male or female and have "non-syndromic" intellectual disabilities, meaning they don't have altered anatomical development or other features such as autism.

Defining Intellectual Disability (ID)

Intellectual Disability (ID)

Intellectual disability (ID) is a term used when a person has certain limitations in cognitive functioning and skills, including communication, social, and self-care skills. These limitations can cause a child to develop and learn more slowly or differently than a typically developing child. Intellectual disability can happen any time before a child turns 18, even before birth. According to the American Association of Intellectual and Developmental Disabilities, an individual has an intellectual disability if they meet three criteria:

IQ is below 70-75.
The condition manifests itself before the age of 18.
There are significant limitations in two or more adaptive areas (skills needed to live, work, and play in the community, such as communication or self-care).

Intellectual disability affects about 2-3% of the general population. Seventy-five to ninety percent of the affected people have a mild intellectual disability. Non-syndromic or idiopathic cases account for 30 to 50% of these cases. A genetic disorder causes about a quarter of cases, and about 5% of cases are inherited from a person's parents. Cases of unknown cause affect about 95 million people as of 2013.

Introduction

Mutant flies shed light on inherited intellectual disability - clumsy fruit flies with poor posture help an international team of scientists understand inherited intellectual disability in humans - and vice versa.

Main Digest

The flies can't hold their wings tightly against their bodies and have trouble with flying and climbing behaviors because they have mutations in a gene called dNab2. In humans, mutations in the same gene (with a clunkier name, ZC3H14) have been found to cause intellectual disability (ID) in studies of some Iranian families. ID describes the condition that was previously called mental retardation.

The protein encoded by Nab2/ZC3H14 appears to be part of a group of proteins, including the one disrupted in fragile X syndrome, that regulates brain cell function by binding RNA.

Cross-species comparisons of Nab2/ZC3H14's function shed light on how brain cells regulate genes by controlling the length of their RNA "tails." The results are published online in the Proceedings of the National Academy of Sciences Early Edition.

This unusual collaboration brought together investigators from Emory University School of Medicine in Atlanta, the Max Planck Institute for Molecular Genetics in Berlin, and the University of Social Welfare and Rehabilitation Sciences in Tehran.

The paper's co-first authors are Emory graduate student Chang Hui Pak and Max Planck postdoc Masoud Garshasbi, with senior authors Andreas Kuss, Ph.D., group leader at the Max Planck Institute, and Anita Corbett, Ph.D., professor of biochemistry and Ken Moberg, Ph.D., assistant professor of cell biology at Emory University School of Medicine.

At Emory, Corbett had studied Nab2 in yeast since the 1990s. Her laboratory teamed up with Moberg to examine the gene's function in fruit flies. Pak, a student in Corbett's and Moberg's labs, generated flies with mutations in dNab2.

What made those flies easy to spot, next to regular flies, was that the mutant flies kept their wings stretched out. Healthy flies hold their wings folded together over their bodies. Moberg says several mutations affect nerve or muscle development and display this "wings held out" effect in flies.

"At this point, we didn't know if it was a problem with the muscles connected to the wings or with the nerve networks that control those muscles," he says.

Unexpectedly, Corbett received an e-mail in 2009 providing a flash of insight. The Berlin/Tehran team studied families in Iran where cousins marry, looking for genetic mutations that lead to intellectual disability.

"It has been more straightforward to find mutations that cause ID along the X chromosome because they show up easily in boys - and they don't need to have inherited the defective genes from both parents," Moberg says. "Studying these families with blood-related parents is a way to explore new ground and learn more about genes on other chromosomes that can be linked to ID."

The Berlin/Tehran team had found that a mutation in the ZC3H14 gene showed up in two independent family trees affected by intellectual disability. Affected individuals can be male or female and have "non-syndromic" intellectual disability, meaning that they don't have altered anatomical development or other features such as autism.

The mutations in ZC3H14 in affected individuals don't completely wipe out the production of the protein. This may be why the consequences of the human mutation aren't completely fatal. Puzzling, one form of the protein enriched in the brain, is still there, but the forms of the protein found all over the body are gone.

"We suspect that the only reason these people are walking around is that that one isoform is still there," Moberg says.

The discovery of the fly/human link has led to new questions. The protein Nab2/ZC3H14 binds "poly-A tails" (flags the cell puts on RNA molecules when they're ready to be decoded into protein). Moberg says that the protein restricts the length of the tails, which may be more important for some genes than others.

At Emory, scientists are studying mutant flies to figure out more precisely what's wrong with them: which cells in the fly's brain are affected and what genes and processes go awry in these cells. Although the overall structure of the brain and nervous system in mutant flies looks OK, preliminary evidence suggests the mutation alters structures in the brain important for learning and memory. Collaborator Gary Bassell collaborates with Corbett to engineer mice lacking the ZC3H14 gene.

" Although mice may better reflect the human situation, exploring the function of Nab2 in flies first allowed us to be quicker and nimbler in designing experiments," Moberg says.

The Berlin/Tehran team is now examining how common mutations in ZC3H14 are in population groups outside Iran and whether it can account for other forms of intellectual disability.

The Research:

The research was supported by the National Institutes of Health, the German Federal Ministry of Education and Research, the Max Planck Innovation Fund, and the Iranian National Science Foundation. CH Pak et al. Mutation of the conserved polyadenosine RNA binding protein ZC3H14/dNab2 impairs neural function in Drosophila and humans. PNAS Early Edition (2011).

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This peer reviewed publication was selected for publishing by the editors of Disabled World due to its significant relevance to the disability community. Originally authored by Emory University, and published on 2011/07/05 (Edit Update: 2022/08/12), the content may have been edited for style, clarity, or brevity. For further details or clarifications, Emory University can be contacted at emory.edu. NOTE: Disabled World does not provide any warranties or endorsements related to this article.

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