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Genes Identified

Through a collaborative network involving hundreds of doctors around the world who help enroll patients in our study, and a dedicated team of scientists in the lab, we have been fortunate to have identified over a dozen new causes for human disease. These new causes of disease are genes that when mutated lead to specific signs and symptoms in patients that help define new syndromes or clinical conditions. A list and timeline of the genes we have identified recently are listed below.


In 2013, Naiara Akizu, Vincent Cantagrel, together with collaborators at Broad Institute and a host of amazing international clinical colleagues, identified a new syndrome with pontocerebellar hypoplasia with a unique appearance to the brainstem due to mutations in the AMPD2 gene. The AMPD2 gene encodes for AMP-deaminase 2, one of three paralogues mediating the conversion of AMP to IMP. Through studies of the patient-derived neural stem cells and knockout mice, we uncovered a unique metabolic disturbance in the genaration of one of the main energy sources of the cell: the synthesis of GTP. We uncovered a way to bypass this metabolic block using a over-the-counter nutitional supplement call AICAR. Thus we identified a new potentially treatable pediatric neurodegenerative condition not previously considered treatable.


In 2013, Farid Radmanesh, together with collaborators at Yale and the Broad Institute, identified a new syndrome displaying a constellation of brain malformations including cortical gyral and white matter abnormalities, brainstem hypoplasia and occipital encephalocele.The clinical appearance was similar to patients with the disease "Muscle-Eye-Brain" disease but our patients displayed only brain defects. The gene found mutated in these families was LAMB1, encoding a member of the laminin class of proteins involved in attachment of radial glia to the brain surface during development. This is one of the first forms of "cobblestone" lissencephaly without involvement of muscle.


Naira Akizu and collaborators at UCSF and Children's Hospital of Philadelphia identified a new syndrome consisting of defects in the development of the corpus callosum in four families from the Middle East, and implicated a specific mutation in the c12orf57 gene in the disorder.The protein is entirely novel, and displays no known functional domains, suggesting we have alot to learn about this new factor. Interestingly, the degree of corpus callosum involvement was variable, even within a family, and the same gene was implicated by the Al-Kuraya lab as causing a colobomatous microphthalmia syndrome, suggesting clinical pleiotropy and genetic modifiers.


In 2012, Gaia Novarino, together with collaborators at Yale, Indiana University, and the Broad Institute, identified a new potentially treatable form of autism and epilepsy. The gene mutated is BCKDK, encoding a protein involved in branched chain amino acid metabolism. The results suggest that this form of disease should be treatable with simple dietary supplementation. We have engaged patients with a clinical trial to determine if there is improvement on treatment. This is the first potentially treatable form of autism.


In 2012, Jeong Ho Lee and Jennifer Silhavy, together with collaborators at UCSD, UCLA and the Broad Institute, uncovered the molecular cause for hemimegalencephaly, a rare and devistating condition in which half of the brain is massive enlarged. In this condition, for unknown reasons, one cerebral hemisphere is severely malformed and enlarged, leading to severe epileptic seizures and mental impairment, the treatment for which is surgical removal of the hemisphere. We identified mutations in these three genes in patients who had undergone surgical resection. Because these genes all function on the same biochemical pathway, and there are drugs that can modulate this pathway, so this discovery may lead to changes in the way physicians approach patients with HME.


In 2012, Fernando Martinez, Jeong Ho Lee and others identified the NSUN2 gene as mutated in Dubowitz syndrome, a unique neurogenetic condition without known causes. Dubowitz syndrome was first described by Victor Dubowitz in London in 1965, characterized by familial low birthweight, dwarfism with unusual facies and skin eruption, then expanded to enclude features such as microcephaly, congenital heart defects and immunological abnormalities. Working with Dr. Lihadh Al-Gazali in the UAE, and using exome sequencing, we uncovered the connection with NSUN2, encoding an RNA methyltransferase, responsible for methylation of key residues in specific transfer RNAs. Our discovery of a mutation in NSUN2 suggests RNA methylation as an important step in neurodevelopment.


In 2012, Jeong Ho Lee and others identified the TMEM138 gene as mutated at Joubert syndrome locus 2. This was very surprising because we had previously identified mutations in the TMEM216 gene at the same locus, but half of the patients lacked mutations in that gene. We found that the TMEM138 gene was mutated in the remaining half of the patients, and that the two genes co-evolved and co-function in a newly emerged cis-regulatory module. The two TMEM genes function to modulate vesicular transport to the primary cilium, critical for ciliogenesis.


In 2011, Ji Eun Lee, in collaboration with an international team studying Joubert syndrmoe, identified mutations in the CEP41 gene causing a new genetic form of Joubert syndrome. We found that the CEP41 gene is required in both mouse and zebrafish for development and plays a critical role in tubulin post-translational modification at the primary cilium.


In 2010, Vincent Cantagrel led an international collaborative effort to identify the SRD5A3 gene as mutated in a new form of congenital disorder of glycosylation. We found that the SRD5A3 protein is the long-sought polyprenol reductase, and in its absence, there is failure to synthesize dolichol, a precursor for protein glycosylation.


In 2010, Jeong Ho Lee, in collaboration with the Valente, Attie-Bitach, and Johnson labs, identified the TMEM216 gene as the cause for Joubert syndrome and Meckel syndrome locus 2 disease. Surprisingly, a single mutation in this gene appears to be the sole cause for specific patient populations, leading to the possibility of prenatal diagnosis and mutation carrier screening.


In 2009, Stephanie Bielas, Jennifer Silhavy and others demonstrated the surprising finding that mutations in the gene INPP5E, encoding a 5-phosphatase for phosphatidylinositol 3,4,5 triphosphate, causes Joubert syndrome when mutated. This was the first connection between the phosphatidylinositol pathway and the ciliopathies, and suggests that treatments for the ciliopathies might be developed that targeted this pathway. Concurrently, the Schurmans lab in Belgium created a knockout mouse and found ciliopathy phenotypes, linking the gene to this function in different organisms.


In 2008, Vincent Cantagrel and others in our lab identified the gene ARL13B in JS patients. Patients with a mutation in this gene present with the classical form of JS. The discovery has linked JS to signaling defects in the Sonic Hedgehog pathway.


The second gene identified by our lab for Joubert syndrome was discovered with Enza Maria Valente et al., in 2006 in concurrence with a group from the University of Michigan (Sayer et al., 2006). The gene is called CEP290. Patients with mutations in this gene most commonly present with additional eye and kidney involvment. This is the most commonly mutated gene in congenital retinal blindness and the most commonly mutated gene in the cerebello-oculo-renal form of Joubert syndrome.


In 2004, Tracy Dixon-Salazar and others in the lab identified the first gene for Joubert syndrome along with a group from Harvard (Ferland et al., 2004). The gene is called AHI1 or Jouberin. Patients with a mutation in this gene usually present with the classical form of JS. This is among the most commonly mutated gene in the ocular form of Joubert syndrome.