The Evolutionary History of the LINCL Gene in the Founder Population of Newfoundland
Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL) is one of a group of hereditary neurodegenerative disorders described worldwide and characterized by the intralysosomal accumulation of autofluorescent lipopigments known as ceroid-lipofuscin. It presents in children at 2-4 years old as seizures followed by progressive dementia and early death. The childhood neuronal ceroid lipofuscinoses are the most common pediatric neurodegenerative diseases, with an estimated incidence of 1/100,000 in the general population. The incidence is higher in genetically homogeneous populations such as the Finnish (5/100,000) and may be as much as 20/100,000 in the island population of Newfoundland.
LINCL follows an autosomal recessive pattern of inheritance involving mutations in the CLN2 gene. CLN2 is a 13-exon, 12-intron 6.65 kb gene encoding a lysosomal tripeptidal peptidase. Because a range of variants in the CLN2 gene are associated with LINCL, it is important to conduct genotype-phenotype correlations between particular mutations and the exact manifestation of the disease. Although there is no current cure for LINCL, this aids in diagnosis, prognostication, accurate genetic counseling and development of future therapies. As part of such an investigation led by Sue Moore at MUN’s Faculty of Medicine, we have obtained the complete DNA sequence of the CLN2 gene in 59 individuals from 21 Newfoundland families clinically diagnosed with LINCL. We have identified 17 polymorphisms in the CLN2 gene among these individuals, 10 of which occur in introns or otherwise do not affect the function of the protein product of the gene. The remaining seven include three previously described mutations known to be associated with LINCL, and four new mutations that alter protein function, one radically.
The 10 “silent” mutations are informative about the molecular diversity of the CLN2 gene and the evolutionary history of the mutations in the founding island population of Newfoundland. This population comprises approximately 500,000 individuals that are the direct descendants of about 20,000 settlers from England, Ireland and France who founded small outport fishing villages around the coast of the island in the late 1700s. Geographic isolation and religious segregation limited genetic exchange among these settlements and the accompanying genetic drift in small populations has led to expectations of loss of genetic diversity within the Newfoundland population.
Using coalescent theory, we can distinguish between a so-called “founder hypothesis” and other explanations such as heterozygote advantage in causing the high frequency of disease alleles in small isolated populations, and to age these alleles, by analyzing the molecular diversity of the locus. The results from this study will allow fine-tuning in the implementation of genotype-phenotype correlations to LINCL diagnosis, prognostication, and counseling, and will enhance our understanding of the unique genetic structure of the Newfoundland population.