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Researcher ProfilesCategory: Research Database; Topic: Researcher Profiles
Posted on: Aug 24, 2009; by ming Printer-friendly page
 Peter Jezewski
 

Peter Alan Jezewski, DDS, PhD
Research Associate
Department of Cytokine Biology

Instructor, Oral Medicine, Infection and Immunity,
Harvard School of Dental Medicine

email: pjezewski at forsyth.org

University of California at Los Angeles, B.A., 1976, Biology

University of California at Los Angeles, M.A., 1981, Molecular Biology

University of California at San Francisco, D.D.S., 1984, Dentistry

University of Iowa, Certificate, 2002, Periodontology

University of Iowa, Ph.D., 2005, Oral Science/Genetics

 
Study the Mendelian forms of human diseases to help understand the more common, complex diseases
The different inheritance patterns of human diseases can often determine the research approach needed to identify the affected gene(s). The study of common diseases, like gum disease or the most common birth defects, is certainly relevant to the general public because they impact so many families. However, these studies are costly since they require that many participants be followed over many years. They are also difficult to study from the strictly genetic standpoint since recent research suggests they are caused by the interactions of many mild mutations with environmental risk factors, and are therefore called "complex diseases". These mild mutations are quite difficult to distinguish from normal genetic variations.

A more efficient approach to understanding these complex diseases is to study the simpler forms of the disease that are inherited in a Mendelian (single gene) fashion. This means that just one (dominant) or two (recessive) defective versions of a single gene can cause disease. Mendelian diseases can also be linked with the X or Y sex chromosomes. The mutations that cause Mendelian syndromes are therefore much stronger, with more obvious effects on a given individual. Thus, the study of single gene disorders with stronger mutations can also offer insight into the cause or pathogenesis of the common forms of disease.

Study of complex disease mutations identified among nonsyndromic orofacial clefting patients requires functional analysis in an animal model, the zebrafish
One of the most common birth defects is cleft lip and palate, also called orofacial clefting. When cleft lip and palate occurs with other clinical pathologies in one individual it is considered to be a 'syndrome'. When a patient only has orofacial clefting by itself this is considered to be a 'nonsyndromic' form of this disease. The nonsyndromic form is much more common than the syndromic form. Nonsyndromic orofacial clefting occurs in 1 in 700 births world wide, and represents about 70% of all infants born with a cleft lip and palate. The other 30% (the syndromic) is made up of several hundred rare Mendelian, chromosomal, teratogenic and sporadic disorders that have other phenotypic features besides clefts.

Many reports have found genetic markers that are associated with the common diseases like orofacial clefting but the actual "disease mutation" can only be identified after exhaustive genetic and functional testing. This is so because these genes have very mild or moderate mutations, that are very difficult to disintguish from normal variation.In these cases, the biological processes through which the gene mutations actually induce the development of the disease has still not been demonstrated. One way to evaluate the effects of these gene mutations is to study their effects in a simple vertebrate (an animal with a backbone), like the zebrafish. The zebrafish, Danio rerio, is a model system to study birth defects that affect the face since its development is so well understood.

Among the genes identified with mutations found only in orofacial clefting patients are the MSX1 and the PVRL1 genes. Study of the MSX1 gene in over 1000 clefting cases from multiple populations identified rare mutations within conserved coding and noncoding sequences, not found in over 500 matched controls. Novel common mutations were also identified in linkage disequilibrium (statistically associated) with the disease. Similar testing of the PVRL1 gene, in more than 800 families from different populations, also identified both rare and common disease associated alleles. While these genetic results are suggestive, ultimately functional testing of these mutations in the zebrafish is needed and is ongoing in my laboratory. Such functional evaluation will offer further validation to the genetic results and insight into the disease pathogenesis.

Blepharocheilodontic Syndrome is a Mendelian orofacial clefting syndrome
The Blepharocheilodontic syndrome is one of many rare clefting syndromes of unknown genetic cause. It is characterized by three main features: defects of the eyes/ eyelids (blepharo), lips (cheilo), and teeth (dontic). The facial clefting is usually the most severe bilateral cleft of the primary and secondary palates. In families it is inherited in an autosomal dominant fashion. My laboratory has initiatied a study of this syndrome that is in progress, with investigators at Children's Hospital of Boston and Philadelphia, UC Irvine Medical Center and University College London.. We hope that this work will ultimately provide clues towards preventive strategies for this particular syndrome and also the more common forms of orofacial clefting.

Local aggressive periodontitis is a Mendelian form of periodontitis
Approximately 10-15% of the adult population a relatively large number - are at risk to experience severe periodontal attachment loss (the common/ complex form of periodontitis), while the Mendalian forms like Papillon-Lefevre Syndrome or Chediak-Higashi Syndrome are individually rare.

One of the Mendelian forms of periodntal disease is called localized aggressive periodontitis (LAgP). It is inherited in an autosomal dominant fashion. LAgP progresses rapidly and usually is observed by the start of the teenage years. At this time severe bone loss is found mainly around the incisors and first molars. Several studies have suggested a much higher prevalence of this disease among those of African descent. To facilitate identification of the gene or genes for this disorder, my laboratory is involved in the collection of LAgP case and control DNA samples, with investigators at Virginia Commonwealth University, Boston University, and the Harvard/MIT Broad Institute. Admixture genetic mapping techniques will be used to examine the genetic association of population and disease alleles. The hope is that finding the causative gene(s) will provide treatment and prevention strategies for these patients as well as provide clues to the genetic mutations that predisopose to the more common forms of periodontitis.

Selected Publications
Finnerty J, Mazza M, Jezewski PA. 2009. Domain duplication, divergence and loss events in vertebrate Msx paralogs reveal phylogenetically informed disease markers. BMC Evolutionary Biology. In press.

Jezewski PA, Fang PK, Payne-Ferreira TL, Yelick PC. 2008. Zebrafish Wnt9b synteny and expression during first and second arch, heart, and pectoral fin bud morphogenesis. Zebrafish. 5(3):169-77

Avila JR, Jezewski PA, Vieira AR, Orioli IM, Castilla EE, Christensen K, Nepomuceno B, Daack-Hirsch S, Romitti PA, Murray JC. 2006. PVRL1 variants contribute to nonsyndromic orofacial clefting in multiple populations. Am. J. Med. Genet. 140(23):2562-70.

Suzuki Y, Jezewski PA, Machida J, Watanabe Y, Shi M, Cooper ME, Viet LT, Tin NTD, Hai H, Natsum N, Shimozato K, Marazita ML, Murray JC. 2004. In a Vietnamese population MSX1 variants vontribute to cleft lip and palate. Genet. Med. 6(3):117125.

Jezewski P, Vieira A, Nishimura C, Ludwig B, Johnson M, O'Brien S, Daack-Hirsch S, Schultz R, Weber A, Nepomucena B, Romitti P, Christensen K, Orioli I, Castilla E, Machida J, Natsume N, Murray J. 2003. Complete sequencing shows a role for MSX1 in nonsyndromic cleft lip and palate. J. Med. Genet. 40(6) :399407.

  Posted on: Monday, August 24, 2009 - 09:15 PM; by: ming

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