Vorhees-Williams-Skelton Lab

  • Basic Research in Angelman Syndrome in Neurology

    Angelman syndrome (AS) was first characterized by Dr. Harry Angelman in 1965 after he noticed similar phenotypes in several of his pediatric patients.  Dr. Angelman was a pediatrician who had three children under his care with similar characteristics including developmental problems, seizures, and ataxia.  The children, originally described as having puppet-like features because of stiff movements, also had characteristic facial structures, frequent laughter, and autistic-like gestures such as hand-flapping.  Although he suspected a similar underlying cause, the genetic mechanisms of the disorder were unknown until recently. As more children were diagnosed, the name was changed to Angelman syndrome.  AS is often misdiagnosed, particularly before patients reach three years of age, so the actual incidence may be higher than originally estimated.  Several disorders present with similar symptoms, leading to the misdiagnosis of AS.  Common disorders that may mimic certain phenotypes associated with AS include Rhett syndrome in girls, ataxic cerebral palsy, and severe autism.  AS children have intellectual disability and loss of language and often cannot perform the routine functions of daily living and self-care.  These problems remain throughout life and at present there is no treatment.  AS is estimated to occur in 1 in every 10,000 births.

    Understanding Gene Silencing in a Model of Angelman

    AS is unique because it is one of only a few known imprinting disorders.  Although it is widely accepted that imprinting of the enzyme, UBE3A, occurs through the generation of a long, non-coding antisense mRNA transcript (UBE3A-ATS), little is known about function of the antisense molecule but the existence of this silencing signal may suggest that it  has function beyond silencing the paternal UBE3A allele.  In collaboration with Dr. Trainer, we are exploring the use of microRNA to alter the expression of UBE3A-ATS and examine the effects on paternal UBE3A expression to answer basic questions about other targets of the antisense transcript and its regulatory mechanisms.

    Treatment Approaches for AS in a Mouse Model

    Another is to test currently FDA-approved pharmaceuticals developed for other disorders that may be used to ameliorate the symptoms of AS.  In 2007, Dr. Edwin Weeber’s lab found that increasing CaMKII activity in the AS mouse model was sufficient to rescue the phenotype.  The rescue improved seizures, learning and memory, and motor coordination.  CaMKII activity is decreased in Ube3a KO mice resulting from increased inhibitory phosphorylation, a possible result of reduced phosphatase activity.  Based on this observation, we are investigating drugs known to increase phosphatase activity to determine if they increase CaMKII activity and improve the phenotype seen in untreated Ube3a KO mice.