A team of researchers that includes 2013 NARSAD Young Investigator Grantee Christelle Golzio, Ph.D., has identified the causal gene for a rare neurodevelopmental disease, and in the process shed light on how mutations in commonly expressed genes can result in a wide range of serious illnesses that start at the beginning of life, including autism spectrum disorder (ASD).

Dr. Golzio, of the Center for Human Disease Modeling at Duke University Medical Center, and colleagues from Duke and the Rutgers Robert Wood Johnson Medical School, worked with samples from a single family, at least three of whose members—spanning two generations—shared a number of severe neurological and developmental symptoms. The disorder included symptoms of delayed development, recurrent fevers, seizures, and slow growth, as well as poor head growth that resulted in microcephaly (head size much smaller than typically developing children the same age). One boy and two of his uncles shared many of these symptoms, pointing the researchers to look for a mutation on the X-chromosome. Such "X-linked" mutations can be carried by both males and females, but with few exceptions cause symptoms only in males.

Working with genetic samples donated by nine members of the family, including those affected, the team of researchers used advanced genetic sequencing techniques in a series of experiments that led them to propose, in a paper published in the journal Genetics on October 1st, that the misspelling of a single DNA “letter” in the human genome is the likely root cause of the entire constellation of symptoms.

That misspelling—a “single nucleotide” mutation—was found to affect production of a protein called RPL10, whose activity is both commonplace and essential in the developing central nervous system. Dr. Golzio and colleagues were aware that the same genome area containing the spelling error had been associated in prior studies with ASD, another “X-linked” disorder. The RPL10 protein forms a part of the structures called ribosomes in cells. Ribosomes take coded instructions from genes and use them to manufacture proteins. Proteins do the “work” in cells and are the physical building blocks of bodily tissue and vital organs.

“There are an abundance of developmentally important genes on the X chromosome, and to date, more than 100 have been associated with ASD, intellectual disability, microcephaly or seizures,” the team writes, mainly in boys with one copy of the mutation “and to a lesser extent in their carrier mothers.”

By inserting the mutant gene into a model organism—a zebrafish embryo—Dr. Golzio and colleagues confirmed that activity of RPL10 is augmented in the “front” portion of the embryos, and that a reduction in its expression correlates with reduced head size. The results “add to an accumulating repertoire of ubiquitously expressed genes” that produce effects in very specific body areas in early development, the team notes. While identifying the mutation does not mean a cure is now available for the boy and his uncles, the new finding provides a crucial first step for the possibility of developing treatments.

Read the abstract of this research paper.