Driscoll, Daniel J.: Professor

ANGELMAN and PRADER-WILLI SYNDROMES: GENOMIC IMPRINTING in 15q11-q13

The phenomenon of genomic imprinting is the differential modification of the maternal and paternal genetic contributions to the zygote, resulting in the differential expression of parental alleles during development and in the adult. A disturbance in genomic imprinting in humans has been shown to play a role in several birth defects, genetic diseases and cancers. In humans, the most convincing demonstration of an imprinted region is at chromosome 15q11-q13 with a deficiency of the maternal region resulting in the Angelman syndrome (AS) and a deficiency of the paternal region resulting in the Prader-Willi syndrome (PWS). These two syndromes, which share a common chromosomal deletion, (see fig 1) are vastly different clinically.AS is characterized by lack of speech, seizures, severe mental retardation, ataxia and a unique neurobehavior including a very happy disposition. PWS patients have obesity, mild mental retardation, hypotonia, hypogonadism, short stature and an obsessive-compulsive personality. As neonates the PWS patients have great difficulty feeding, but between 18-36 months of age they become hyperphagic and obese.

Our team in Pediatric Genetics has assembled one of the best characterized panels of AS and PWS patients in the world, allowing us to pursue several avenues of research regarding mammalian genomic imprinting. Using AS (paternal allele only) and PWS (maternal allele only) we are able to identify differences in DNA methylation, gene expression, DNA replication and chromatin structure between the maternal and paternal alleles in the imprinted 4 megabase 15q11-q13 region.

We have recently identified several genes that demonstrate a DNA methylation imprint distinguishing the maternally and paternally inherited alleles. These genes (SNRPN , MKRN3 and NECDIN) have been characterized and are only expressed from the paternally inherited allele. Prader-Willi patients lack expression of these genes. The SNRPN polypeptide (SmN) is involved in splicing pre-mRNA, the MKRN3 gene encodes a zinc finger protein and NECDIN is mainly expressed in post-mitotic neurons. All these genes have a CpG island at their 5′ end which is unmethylated on the expressed paternal allele and methylated on the repressed maternal allele. In the SNRPN gene, we have identified a putative DNA methylation imprinting signal that is first initiated in male and female gametogenesis.

Future research in the laboratory will focus on:

1) understanding the role that the paternal-only expressed genes play in the pathogenesis of PWS;
2) exploring the factors involved in genomic imprinting in somatic and germ cells;
3) using AS and PWS patients as a springboard to understand obesity, verbal communication and neurobehavior and
4)assessing the efficacy of growth hormone (see fig 3) and other hormonal treatments for children and adults with PWS.

The projects in the lab are currently funded by grants from the NIH and the Hayward Foundation, as well as an endowed professorship.

Education:

Medical Genetics Postdoctoral Fellow, Johns Hopkins  Hospital

Pediatric Residency, Johns Hopkins Hospital

M.D. Albany Medical College

Ph.D. Indiana University School of Medicine

M.S. Rutgers University

A.B. Colgate University

Board Certifications:

Pediatrics,  Medical Genetics – Clinical; Molecular; and Cytogenetics

Citations

Awards, Professional Service:

NIH Predoctoral Trainee,  Indiana University School of Medicine  The Richard T. Beebe Award in Medicine, Albany Medical  College.  NIH Postdoctoral Fellowship, The Johns Hopkins Hospital.  Finalist, Postdoctoral Basic Research Award, American  Society of Human Genetics.  Basil O’Connor Starter Scholar Research Award, March of Dimes.  The John T. and Winifred M. Hayward Professorship in  Genetics Research, University of Florida.  NIH K24 Midcareer Patient-Oriented Investigator Award. UFRF Professorship Award. Society of Scholars, Johns Hopkins University.

Teaching Responsibilities:

BMS 5003 Medical Aspects of Genetics , GMS 7191 Research Conference, GMS 7979 Advanced Research, GMS 7980 Doctoral Research