Pineda-Trujillo, N.G.; (2005) Linkage analysis of Mendelian forms of complex disorders in a South American population. Doctoral thesis , University of London.

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Abstract

Genetic analysis in Mendelian forms of complex disorders may help increase our understanding of the biology of these disorders. Genes identified in Mendelian forms could also be relevant for disease susceptibility of the more common forms of the disease. I have studied a collection of patient samples from Antioquia, Colombia, including Mendelian and sporadic forms of four well characterized diseases: Parkinson's PD , Generalized epilepsy with Febrile Seizures Plus GEFS+ , Batten's disease and Type 1 Diabetes T1D . In addition, I studied two extended families with unusual disorders. Affected individuals in one family presented with episodic crisis of abdominal pain, possibly corresponding to Abdominal Epilepsy AE . Patients from the other family presented with a multiform movement disorder MMD , at times diagnosed as Parkinson's or Huntington's disease. Brain pathology from an affected individual showed the presence of iron deposits as a key finding. I subsequently performed linkage analysis of these families. Initial analysis focused on testing linkage to known candidate genes or regions. If these proved negative or if no candidate gene/region was available, a genome scan was then conducted. I have excluded all previously known genes/loci in two out of six families with GEFS+. The remaining four families were found linked to either SCN1A or GABRG2 genes. In a family with Parkinson disease, a novel mutation was identified in exon 3 of the PARK2 gene. It was not possible to establish whether a common chromosome was involved in the same mutation reported separately by both a Spanish group and we since those mutant chromosomes are presenting a very different haplotype in both populations. In Batten disease, the first mutation in CLN5 gene outside Europe was found, which leads to a variant of the juvenile form rather than to a late infantile presentation of Neuronal Ceroid Lipofuscinosis. For T1D, a haplotype on chromosome 2 was found to be segregating with the disease in a large family with autoimmune T1D. Regarding the two genome wide scans, in MMD, suggestion of linkage to two functionally candidate genes was found. These are the Neurogolobin (NGB) and the Ferritin heavy polypeptide (FTH1) genes. In Abdominal epilepsy, a locus was identified on chromosome 8 and fine mapping led to the identification of a critical region extending 1.3 Mb at 8ql3.

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