Evolved, mutated gene module linked to Joubert syndrome

A team led by researchers at the University of California, San Diego School of Medicine reports that newly discovered mutations in an evolved assembly of genes cause Joubert syndrome, a form of syndromic autism.

The findings are published in the January 26 online issue of Science Express.

Joubert syndrome is a rare, recessive brain condition characterized by malformation or underdevelopment of the cerebellum and brainstem. The disease is due specifically to alterations in cellular primary cilia – antenna-like structures found on most cells. The consequence is a range of distinct physical and cognitive disabilities, including poor muscle control, and mental retardation. Up to 40 percent of Joubert syndrome patients meet clinical criteria for autism, as well as other neurocognitive disorders, so it is considered a syndromic form of autism.

The cause or causes of Joubert syndrome are not well-understood. Researchers looked at mutations in the TMEM216 gene, which had previously been linked to the syndrome. However, only half of the expected Joubert syndrome patients exhibit TMEM216 gene mutations; the other half did not. Using genomic sequencing, the research team, led by Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego, broadened their inquiry and discovered a second culprit: mutations in a neighboring gene called TMEM138.

“It is extraordinarily rare for two adjacent genes to cause the same human disease,” said Gleeson. “The mystery that emerged from this was whether these two adjacent, non-duplicated genes causing indistinguishable disease have functional connections at the gene or protein level.”

Through evolutionary analysis, the scientists concluded that the two TMEM genes became joined end-to-end approximately 260 million years ago, about the time some amphibians began transitioning into land-based reptiles. The connected genes evolved in tandem, becoming regulated by the same transcription factors.

What is Joubert Syndrome?
Joubert syndrome is a rare brain malformation characterized by the absence or underdevelopment of the cerebellar vermis - an area of the brain that controls balance and coordination. The most common features of Joubert syndrome in infants include abnormally rapid breathing (hyperpnea), decreased muscle tone (hypotonia), jerky eye movements (oculomotor apraxia), mental retardation, and the inability to coordinate voluntary muscle movements (ataxia). Physical deformities may be present, such as extra fingers and toes (polydactyly), cleft lip or palate, and tongue abnormalities. Kidney and liver abnormalities can develop, and seizures may also occur.. Most cases of Joubert syndrome are sporadic (not inherited). In some families, however, Joubert syndrome appears to be inherited in an autosomal recessive manner (meaning both parents must have a copy of the mutation) via mutation in a number of genes, including NPHP1, AHI1, and CEP290.

“Prior to this transition, the two genes had wildly different expression levels,” said Jeong Ho Lee, MD, PhD, and first author of the study. “Following this transition, they became tightly co-regulated. Moreover, we found that the two encoded proteins coordinate delivery of factors key for cilia assembly.”

Symptoms
The symptoms of Joubert syndrome are related to the underdevelopment of an area of the brain called the cerebellar vermis, which controls balance and muscle coordination. The symptoms, which may range from mild to severe depending on how much the brain is underdeveloped, may include:

Periods of abnormally rapid breathing (episodic hyperpnea), which may seem like panting jerky eye movements (nystagmus) characteristic facial features such as drooping eyelids (ptosis), open mouth with protruding tongue, low-set ears mental retardation difficulty coordinating voluntary muscle movements (ataxia).
Periods of abnormally rapid breathing (episodic hyperpnea), which may seem like panting jerky eye movements (nystagmus) characteristic facial features such as drooping eyelids (ptosis), open mouth with protruding tongue, low-set ears mental retardation difficulty coordinating voluntary muscle movements (ataxia) Other birth defects such as extra fingers and toes (polydactyly), heart defects, or cleft lip or palate may be present. Seizures may also occur.

Gleeson said the findings suggest the human genome has evolved to take advantage of fortuitous ancestral events like gene translocations to better coordinate gene expression by assembling into specific modules. When these modules are disrupted, however, neurodevelopmental diseases may result.

Joubert syndrome prognosis?
The prognosis for infants with Joubert syndrome depends on whether or not the cerebellar vermis is partially developed or entirely absent. Some children have a mild form of the disorder, with minimal motor disability and good mental development, while others may have severe motor disability and moderate mental retardation.

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Provided by University of California - San Diego

 

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