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dc.contributor.supervisor Wrogemann, Klaus (Biochemistry and Medical Genetics) Greenberg, Cheryl (Pediatrics and Child Health) en
dc.contributor.author Frosk, Patrick
dc.date.accessioned 2006-06-13T13:33:00Z
dc.date.available 2006-06-13T13:33:00Z
dc.date.issued 2006-06-13T13:33:00Z
dc.identifier.uri http://hdl.handle.net/1993/249
dc.description.abstract Limb girdle muscular dystrophies (LGMDs) are a clinically and genetically heterogeneous group of myopathies characterized by weakness and wasting of the proximal musculature. There are currently seventeen loci associated with different LGMDs, seven with an autosomal dominant mode of inheritance (LGMD1A–1G) and 10 with an autosomal recessive mode of inheritance (LGMD2A– 2J). The cumulative worldwide prevalence of LGMD is thought to be ~1/15,000. In the Hutterite population of North America there is an over-representation of autosomal recessive LGMD with a prevalence estimated to be >1/400. The objective of this work was to delineate the genetic basis of LGMD in this large genetically isolated population. A genome-wide scan was performed on Hutterite LGMD patients and their families in order to locate the mutant gene. This allowed us to identify a novel locus at chromosome region 9q31-33 that was named LGMD2H. Extensive haplotyping and mutation screening led to the discovery of c.1459G>A in TRIM32 as the causative mutation of LGMD2H. We then found that this same mutation was the cause of another previously described myopathy in the Hutterites, sarcotubular myopathy (STM)[reference awaiting publishers decision]. Analysis of the TRIM32 gene product revealed that it is a potential E3-ubiquitin ligase, is expressed in many human tissues including muscle and brain, and has a punctate cytoplasmic distribution. During the analysis of the LGMD2H region, it became apparent that there were Hutterite LGMD patients not linked to the LGMD2H locus. In order to identify the causative gene(s) in the remaining families, we performed a genome-wide scan. A locus at chromosome 19q13 was found to correspond to disease inheritance, the site of a previously described LGMD locus, LGMD2I. No causative gene had yet been identified at this locus so haplotyping and mutation screening was performed. We were able to identify c.826C>A in FKRP as the causative mutation in our remaining cohort of LGMD patients. The same mutation has since been found in many other populations, and is apparently a relatively common cause of LGMD. We obtained DNA from 19 non-Hutterite LGMD2I patients of diverse origins with c.826C>A and determined that it is an old founder mutation. There is no further evidence of any other loci causing autosomal recessive myopathy in the Hutterites. With the identification of c.1459G>A in TRIM32 and c.826C>A in FKRP we appear to have delineated the genetic cause of all myopathies of increased prevalence in the Hutterite population. To date, we have been able to provide accurate, non-invasive, diagnosis to over 70 patients and have provided carrier testing to approximately 120 at-risk family members. This kind DNA-based approach is not feasible in the general population due the enormous amount of locus, allelic, and clinical heterogeneity among myopathy patients. en
dc.format.extent 8724165 bytes
dc.format.mimetype application/pdf
dc.language.iso en_US
dc.subject Hutterite en
dc.subject muscular dystrophy en
dc.subject LGMD en
dc.subject TRIM32 en
dc.subject FKRP en
dc.subject Sarcotubular Myopathy en
dc.title Limb girdle muscular dystrophy in the Hutterite population of Manitoba en
dc.type Electronic Thesis or Dissertation en
dc.degree.discipline Biochemistry & Medical Genetics en
dc.contributor.examiningcommittee Triggs-Raine, Barbara (Biochemistry and Medical Genetics) Duckworth, Mary Lynn (Physiology) Ray, Peter (Medical Genetics, University of Toronto) en
dc.degree.level Doctor of Philosophy (Ph.D.) en
dc.description.note May 2005 en


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