Robert D. Nicholls, DPhil

  • Professor of Pediatrics

Rob Nicholls obtained his undergraduate degree at the University of Melbourne (Australia), his doctorate (D.Phil.) at the University of Oxford (UK), and did his postdoctoral research at Children’s Hospital of Boston/Harvard University where he began his research related to Prader-Willi syndrome (PWS). In 1989, his work first identified a role for genomic imprinting in human disease with the discovery of uniparental disomy in PWS.  Nicholls independent faculty career has taken him from the University of Florida (1990-1993), Case Western Reserve University (1993-2000), the University of Pennsylvania (2000-2005), and since 2005 to Pittsburgh. Career highlights include a PWSA lifetime achievement award in 2013 for his work on PWS; in late 2013 he cycled from the Pacific Ocean to the Atlantic Ocean (across the sourthern USA) in 28 days to raise awareness and funds for PWS research. As of 2-26-2020, his publications have been cited 13,182 times with a h-index = 63 (Web of Science) or 18,347 times with a h-index = 69 (Google Scholar). 

Since 1987, the genetic basis of PWS has been the primary research focus of Nicholls. Beyond discovering genomic imprinting in human disease, additional major scientific discoveries in PWS include genetic subclasses, imprinted genes, DNA methylation, imprinting mechanisms, and cellular and animal models. He has also identified several other disease genes: oculocutaneous albinism type 2 (OCA2), the most common form of albinism worldwide especially for people in and of African origin; spastic paraplegia type 6 (SPG6); and mouse juvenile development and fertility (jdf2). Recent studies include work on transcriptional and miRNA regulatory networks in PWS and other genetic diseases. Over the past 20+ years, molecular, epigenetic, endocrine, and pathophysiological studies of animal models of PWS have been a focus. To identify the pathophysiological basis for PWS, he characterized the pig PWS-imprinted genomic domain and developed swine models of PWS using CRISPR/Cas9 genome editing. Similarly, a second, genome-edited pig model was developed for phenylketonuria (PKU). The porcine models of PWS and PKU provide suitable preclinical models for understanding PWS and PKU neuropathophysiology and to explore new therapeutics.

Several years ago, Nicholl’s laboratory demonstrated that progressive, fatal hypoglycemia underlies the severe neonatal failure to thrive of a mouse PWS-deletion model that mimics the PWS neonatal phenotype, with defective pancreatic islet development, increased endocrine cell apoptosis, a functional deficit in insulin secretion with hypoinsulinemia, concurrent hypoglucagonemia, and lack of a counter-regulatory response to hypoglycemia. These findings led to the first clinical recognition of severe hypoglycemic episodes in PWS (and in the pig PWS model). To understand the endocrine deficits in PWS, his laboratory used genome editing to generate hormone-secreting cell lines with the PWS-genetic defect to define cellular and molecular mechanisms critical for secretion of insulin (β- cells), glucagon (α-cells), and other hormones including for GH-secreting pituitary somatotropes. A better understanding of mechanisms of genome-editing for Mb-sized chromosome deletions, inversions, and duplications to model genetic disease has also been gained from the work. The PWS β-cell models replicate the insulin secretion defect previously seen in vivo in the mouse model also demonstrating that deficient insulin secretion is cell autonomous and associated with a profound deficiency of multiple endoplasmic reticulum (ER) chaperone proteins, suggesting a chronic deficit in protein folding and ER exit for hormones and other secretory pathway proteins. This work is now being extended to in vivo studies of pancreatic endocrine cell types in the mouse pancreas and to a novel approach using human pancreatic islets. The work will identify novel mechanisms by which PWS-imprinted genes control the secretion of insulin, glucagon, and other hormones that are dysregulated in PWS and other metabolic diseases, such as type 2 diabetes. An understanding of the deficits of protein secretion regulated by PWS genes is critical for the rational development of novel therapeutics in PWS and type 2 diabetes.

Professional and Scientific Society Memberships

  • American Society of Human Genetics, 1987‑2012
  • American Association for the Advancement of Science, 1988‑2003
  • Prader‑Willi Syndrome Association, 1988‑Present
  • Angelman Syndrome Foundation, 1989-Present
  • British Society Developmental Biology, 1990‑1991
  • Human Genome Organisation, 1991-Present
  • Prader-Willi Florida Association, 1991-1993
  • Prader-Willi Ohio Association, 1993-2000
  • Angelman Syndrome (Ohio) Association, 1993-2000
  • DNA Methylation Society, 1993-1995
  • PanAmerican Society for Pigment Cell Research (PASPCR), 1994-1995
  • International Society of Molecular Evolution, 1996
  • Juvenile Diabetes Foundation International, 1997-1999
  • International Mammalian Genome Society, 1997
  • Federation of American Societies for Experimental Biology (FASEB), 1999-2016
  • American Physiological Society, 2002-2003
  • American Diabetes Association, 2006-2007
  • Society for Neuroscience, 2010
  • American Society of Human Genetics, 2015‑2016

Education & Training

  • BSc (Honors), Biochemistry, University of Melbourne, 1981
  • DPhil, Human Molecular Genetics, University of Oxford, 1986
  • Postdoctoral Research Associate, Human Genetics, Howard Hughes Medical Institute and Harvard Medical School, 1987-1989
  • Honorary Masters Degree, University of Pennsylvania, 2002

Selected Publications

Mikkelsen, T.S., Wakefield, M.J., Aken, B., Amemiya, C.T., Chang, J.L., Duke, S., Garber, M., Gentles, A.J., Goodstadt, L., Heger, A., Jurka, J., Kamal, M., Mauceli, E., Searle, S.M.J., Sharpe, T., Baker, M.L., Batzer, M.A., Benos, P.V., Belov, K., Clamp, M., Cook, A., Cuff, J., Das, R., Davidow, L., Deakin, J.E., Fazzari, M.J., Glass, J.L., Grabherr, M., Greally, J.M., Gu, W., Hore, T.A., Huttley, G.A., Kleber, M., Jirtle, R.L., Koina, E., Lee, J.T., Mahony, S., Marra, M.A., Miller, R.D., Nicholls, R.D., Oda, M., Papenfuss, A.T., Parra, Z.E., Pollock, D.D., Ray, D.A., Schein, J.E., Speed, T.P., Thompson, K., VandeBerg, J.L., Wade, C.M., Walker, J.A., Waters, P.D., Webber, C., Weidman, J.R., Xie, X., Zody, M.C., Broad Institute Genome Sequencing Platform, Broad Institute Whole Genome Assembly Team, Graves, J.A.M., Ponting, C.P., Breen, M., Samollow, P.B., Lander, E.S., Lindblad-Toh, K. (2007) Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences. Nature 447: 167-178

He, M., Rutledge, S.L., Kelly, D.R., Palmer, C.A., Murdoch, G., Majumder, N., Nicholls, R.D., Pei, Z., Watkins, P.A., Vockley, J. (2007) A new genetic disorder in mitochondrial fatty acid beta-oxidation, ACAD9 deficiency. Am. J. Hum. Genet. 81: 87-103

Park, J.H., Stoffers, D.A., Nicholls, R.D., Simmons, R.A. (2008) Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J. Clin. Invest. 118: 2316-2324

Kishore, S., Khanna, A., Zhang, Z., Hui, J., Balwierz, P., Stefan, M., Beach, C., Nicholls, R.D., Zavolan, M., Stamm S (2010) The snoRNA MBII-52 is processed into smaller RNAs and regulates alternative splicing. Hum. Mol. Genet. 19: 1153-1164

Stefan, M., Simmons, R.A., Bertera, S., Trucco, M., Esni, F., Drain, P., Nicholls, R.D. (2011) Global deficits in development, function, and gene expression in the endocrine pancreas in a deletion mouse model of Prader-Willi syndrome. Am. J. Physiol. – Endocrin. & Metab. 300: E909-E922

Henson, B.J., Zhu, W., Hardaway, K., Wetzel, J.L., Stefan, M., Albers, K.M., Nicholls, R.D. (2012) Transcriptional and post-transcriptional regulation of SPAST, the gene most frequently mutated in hereditary spastic paraplegia. PLoS ONE 7(5): e36505

McGuire, T.F., Sajithlal, G.B., Lu, J., Nicholls, R.D., Prochownik, E.V. (2012) In vivo evolution of tumor-derived endothelial cells. PLoS ONE 7(5): e37138

Schiff, M., Haberberger, B., Xia, C., Mohsen, A.W., Goetzman, E.S., Wang, Y., Uppala, R., Zhang, Y., Karunanidhi, A., Prabhu, D., Alharbi, H., Prochownik, E.V., Haack, T., Häberle, J., Munnich, A., Rötig, A., Taylor, R.W., Nicholls, R.D., Kim, J-J., Prokisch, H., Vockley, J. (2015) Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency. Hum. Mol. Genet. 24:

Bell, S., Rousseau, J., Peng, H., Aouabed, Z., Priam, P., Theroux, J-F., Jefri, M., Tanti, A., Wu, H., Kolobova, I., Silviera, H., Manzano-Vargas, K., Ehresmann, S., Priam, P., Hamdan, F., Hettige, N., Zhang, X., Nassif, C., Ghaloul Gonzalez, L., Sebastian, J., Vockley, G., Begtrup, A.G., Wentzensen, I.M., Crunk, A., Nicholls, R.D., Herman, K.C., Deignan, J., Al-Hertani, W., Efthymiou, S., Salpietro, V., Miyake, N., Makita, Y., Matsumoto, N., Au, M., Østern, R., Houge, G., Hafström, M., Fassi, E., Houlden, H., Klein Wassink-Ruiter, J.S., Nelson, D., Goldstein, A., Dabir, T., van Gils, J., Bourgeron, T., Delorme, R., Cooper, G.M., Martinez, J.E., Finnila, C.R., Carmant, L., Lortie, A., Oegema, R., van de Gassen, K., Mehta, S.G., Huhle, D., Abou Jamra, R., Martin, S., Brunner, H., Lindhout, D., Graham, J.M. Jr., Turecki, G., Gravel, S., Mechawar, N., Rossignol, E., Michaud, J.L., Lessard, J., Ernst, C., Campeau, P.M. (2019) Mutations in ACTL6B cause neurodevelopmental deficits and epilepsy and lead to loss of dendrites in human neurons. Am. J. Hum. Genet. 104: 815-834

Ferreira, I.R., Costa, R.A., Ferreira Gomes, L.H., dos Santos Cunha, W.D., Tyszler, L.S., Freitas, S., Llerena Junior, J.C., de Vasconcelos, Z.F.M., Nicholls, R.D., da Cunha Guida, L. (2020) A newborn screening pilot study using Methylation-Sensitive High Resolution Melting on dried blood spots to detect Prader-Willi and Angelman syndromes. Scientific Reports, resubmitted (review required changes to the text only)

Koppes, E., Redel, B.K., Johnson, M.A., Skvorak, K.J., Ghaloul-Gonzalez, L., Yates, M.E., Lewis, D.W., Gollin, S.M., Wu, Y., Christ, S.E., Yerle, M., Leshinski, A., Spate, L.D., Benne, J., Murphy, S., Samuel, M.S., Walters, E.M., Hansen,S.A., Wells, K.D., Lichter-Konecki, U., Wagner, R.A., Newsome, J.T. Dobrowolski, S.F., Vockley, J., Prather, R.S., Nicholls, R.D. (2020) A porcine model of phenylketonuria generated by CRISPR/Cas9 genome editing. Scientific Reports, To be submitted by June 15th 2020.

Full Publication List via NIH PubMed »