*M. CHAHROUR1, T. W. YU1, B. ATAMAN2, M. ALKHAFAJI1, S. R. HILL1, C. R. STEVENS3, M. E. GREENBERG2, S. B. GABRIEL3, C. A. WALSH1; 1Medicine, Div. of Genet., Boston Children's Hospital, Harvard Med. Sch., Boston, MA; 2Neurobio., Harvard Med. Sch., Boston, MA; 3Program in Med. and Population Genet., Broad Inst. of Massachusetts Inst. of Technol. and Harvard Univ., Cambridge, MA
Abstract Body: Autism spectrum disorders (ASDs) are a constellation of neurodevelopmental disorders that affect 1 in 88 children. They are characterized by impaired communication skills, social behavior abnormalities, and stereotypies. Despite the clear genetic component of ASDs, extreme genetic heterogeneity has made it difficult to identify causative genes. We quantified runs of homozygosity in probands from the Autism Genetic Research Exchange (AGRE) collection, in order to identify those with potential recessive mutations due to distant shared ancestry. Whole exome sequencing of the probands with the highest percent of homozygosity in their genomes revealed homozygous, potentially pathogenic recessive mutations in four families. One of the novel ASD candidate genes, UBE3B encodes an uncharacterized E3 ubiquitin ligase that is expressed in human brain. Mutations in several ubiquitin ligases result in ASDs as well as in intellectual disability (ID), including UBE3A, the gene affected in Angelman syndrome, HUWE1, which is mutated in X-linked ID, and UBE3C which has recently been associated with autism risk. A recent study identified complete loss of function mutations in UBE3B underlying a recessive syndrome with severe ID. The UBE3B ASD mutation we identified is a missense change in the HECT domain of the protein consistent with partial loss of function. We show that the transcription of UBE3B is regulated by neuronal depolarization, suggesting potential activity-dependent roles in neurons. We are characterizing the effect of UBE3B disruption on neurons and our preliminary data suggests that UBE3B may have a role in maintaining dendritic complexity. Our strategy of combining homozygosity analysis with whole exome sequence data identifies candidate recessive mutations in autism, and may have broader applicability to other complex, heterogeneous disorders with recessive components.
Lay Language Summary: Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders that affect 1 in 88 children. They are characterized by impaired language and social interactions, and repetitive behaviors. Several genetic mechanisms have been implicated in ASDs, and we decided to focus on recessive mutations that are inherited from both parents. We studied a collection of 1,000 American families with children affected with ASDs, the Autism Genetic Research Exchange (AGRE) collection. For each affected individual, we quantified the percent of the genome that is in the homozygous state, meaning both copies of the genome (the one from the father and the one from the mother) are the same. These regions are likely to carry recessive mutations inherited from the parents. We then sequenced all the genes in the top 16 patients with the highest homozygosity in their genomes to identify any candidate disease-causing mutations. In 4 families, we identified homozygous, potentially pathogenic recessive mutations in novel genes not previously implicated in ASDs. One of these ASD candidate genes, UBE3B encodes a protein expressed in human brain. UBE3B belongs to the family of ubiquitin ligases that add a ubiquitin moiety to substrate proteins to target them for degradation by the proteasome system as part of the normal protein turn over in cells. Mutations in several ubiquitin ligases result in intellectual disability (ID), including UBE3A, the gene affected in Angelman syndrome, and HUWE1, which is mutated in syndromic ID. Two recent studies found that complete loss of function mutations in UBE3B result in a recessive syndrome with severe ID. We have shown that the expression of UBE3B is regulated by neuronal depolarization, suggesting potential activity-dependent roles in neurons. We are characterizing the effect of UBE3B disruption on neurons and our preliminary data suggests that UBE3B may have a role in maintaining dendritic complexity. When we overexpress mutant UBE3B in mouse neurons it results in a decrease in dendritic outgrowth, indicating that the mutant is either partially or completely nonfunctional and it interferes with the normal UBE3B signaling pathway.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit