Genetics researchers find new neurodevelopmental syndrome

Summary: NKAP-related syndrome, a newly identified neurodevelopmental disorder caused by mutations in the NKPA gene, causes developmental delays, intellectual disabilities, behavioral abnormalities, and musculoskeletal problems in children.

Source: CHOP

Researchers have identified a gene mutation that causes developmental delay, intellectual disability, behavioral abnormalities and musculoskeletal problems in children. The newly diagnosed condition, called NKAP-related syndrome, arises from mutations in the NKAP gene, which plays a key role in human development.

“This gene mutation disrupts transcription, the process in which DNA information is converted into RNA,” said study leader Kosuke Izumi, MD, PhD, a clinical geneticist and genetics researcher at Children’s Hospital of Philadelphia. “As my lab continues to explore the function of NKAP in our bodies, we aim to discover clues for future treatments.”

Izumi and co-authors from eight nations published their report of NKAP-related syndrome today in the American Journal of Human Genetics.

The scientists performed exome sequencing on 10 individuals, all children and young adults, with developmental delay, intellectual disability, behavioral problems such as ADHD and aggressive behavior, and tall stature, scoliosis and joint conditions. The subjects’ tall stature and musculoskeletal problems are “Marfanoid”: similar to traits found in the long-known genetic disorder Marfan syndrome.

This shows DNA strands

The exome sequencing pinpointed mutations in the NKAP gene on the X chromosome. Consistent with an X-linked recessive condition, NKAP mutations caused symptoms only in males. The image is in the public domain.

The exome sequencing pinpointed mutations in the NKAP gene on the X chromosome. Consistent with an X-linked recessive condition, NKAP mutations caused symptoms only in males. Further analysis showed that transcription disruption patterns were similar in the patients–a higher proportion of genes were downregulated than upregulated, that is, the mutation “dialed down” the gene’s effects on RNA and proteins. Experiments with zebrafish models revealed similar effects from an analogous mutated gene.

“The function of NKAP in our bodies has been poorly understood,” said Izumi. “We discovered novel functions in brain and musculoskeletal development. Furthermore, we have started a patient registry to collect clinical information on patients with this rare diagnosis. Identifying more patients may help to reveal the full spectrum of medical issues seen in NKAP-related syndrome.”

In addition to providing a definitive diagnosis to a subset of patients with developmental delay and intellectual disability found to harbor this mutation, biological insights may eventually translate into clinical benefits. “As we further investigate biological mechanisms in this syndrome, our goal is to identify molecular pathways to target for future treatments for patients,” added Izumi.

About this neuroscience research article

Source:
CHOP
Media Contacts:
John Ascenzi – CHOP
Image Source:
The image is in the public domain.

Original Research: Closed access
“Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment”. Sarah K. Fiordaliso et al.
American Journal of Human Genetics doi:10.1016/j.ajhg.2019.09.009.

Abstract

Missense Mutations in NKAP Cause a Disorder of Transcriptional Regulation Characterized by Marfanoid Habitus and Cognitive Impairment

NKAP is a ubiquitously expressed nucleoplasmic protein that is currently known as a transcriptional regulatory molecule via its interaction with HDAC3 and spliceosomal proteins. Here, we report a disorder of transcriptional regulation due to missense mutations in the X chromosome gene, NKAP. These mutations are clustered in the C-terminal region of NKAP where NKAP interacts with HDAC3 and post-catalytic spliceosomal complex proteins. Consistent with a role for the C-terminal region of NKAP in embryogenesis, nkap mutant zebrafish with a C-terminally truncated NKAP demonstrate severe developmental defects. The clinical features of affected individuals are highly conserved and include developmental delay, hypotonia, joint contractures, behavioral abnormalities, Marfanoid habitus, and scoliosis. In affected cases, transcriptome analysis revealed the presence of a unique transcriptome signature, which is characterized by the downregulation of long genes with higher exon numbers. These observations indicate the critical role of NKAP in transcriptional regulation and demonstrate that perturbations of the C-terminal region lead to developmental defects in both humans and zebrafish.

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