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Aspartylglucosaminuria (AGU) is a recessively inherited lysosomal disease caused by inadequate aspartylglucosaminidase (AGA) activity. The disease is prevalent in the genetically isolated Finnish population. We have used a new method, solid-phase minisequencing, to determine the frequency of two missense mutations in the AGA gene in this population. In samples from 70% of the Finnish AGU families, we found that the two nucleotide changes were always associated, and they were identified in 98% of the AGU alleles analyzed. Thus, the high prevalence of AGU in the Finnish population is the consequence of a founder effect of one ancient mutation. The identification of asymptomatic carriers by the minisequencing test proved to be unequivocal. The method also allowed quantification of a mutated nucleotide sequence present in less than 1% of a sample. The frequency of AGU carriers in this population was 1/36 when estimated by quantifying the mutated AGU allele in a pooled leukocyte sample from 1350 normal Finnish individuals.

Aspartylglucosaminidase (AGA) is a lysosomal enzyme, the deficiency of which leads to human lysosomal storage disease aspartylglucosaminuria. Here, we describe isolation, chromosomal location, genomic structure, and tissue-specific expression of the mouse Aga gene as well as the intracellular processing of the mouse Aga polypeptide and compare these characteristics to human AGA. The mouse Aga gene was localized to the central area of the B region of chromosome 8, which represents the synteny group in the human chromosome 4q telomeric region where the human AGA gene is located. The mouse gene spans an 11-kb genomic region and contains nine exons and eight introns, which is analogous to the human gene. Furthermore, the exon-intron boundaries of the mouse and human genes are identically positioned. The nucleotide sequence identity of the cDNA and deduced amino acid sequence identity of the protein are 84.4 and 82.4%, respectively. However, the mouse Aga cDNA contains untranslated regions that are shorter than those in the human cDNA, and only one 1.2-kb mRNA transcript is produced in mouse versus two transcripts in human. Expression of the mouse Aga cDNA in COS-1 cells showed that the mouse Aga polypeptide was processed similarly to the human counterpart.

The neuronal ceroid lipofuscinoses (CLNs) are one of the most common progressive encephalopathies of childhood in Western countries. They are divided into three main types: infantile, late infantile, and juvenile. The inheritance of all forms is autosomal recessive, and the biochemical back-ground is totally unknown. The infantile type (CLN1) demonstrates the earliest onset of symptoms and the most severe clinical course. CLN1 is enriched in the Finnish population with incidence of 1:20,000, and only about 50 cases have been reported from other parts of the world. We have collected 15 Finnish CLN1 families with one or two diseased children for a linkage analysis with polymorphic probes randomly localized on human chromosomes. After studying 42 polymorphic protein and DNA markers, we found definitive proof of linkage with three different probes on the short arm of chromosome 1, with maximum lod scores of 3.38 at θ = 0.00 (0.00 – 0.08) for D1S57 (pYNZ2), 3.56 at θ = 0.00 (0.00 – 0.09) for D1S7 (λMS1), and 3.56 at θ = 0.00 (0.00 – 0.11) for D1S79 (pCMM8). With the assignment of the CLN1 gene, our study demonstrates the power of multiallelic VNTR probes in the search for linkage of a rare recessive disorder using limited family material.

Infantile neuronal ceroid-lipofuscinosis (CLN1) is the form of neuronal ceroid-lipofuscinoses (NCL) with the earliest onset of symptoms. The locus of the most common form of these disorders, juvenile NCL (CLN3), has been mapped to chromosome 16. We report here linkage data of the same region in Finnish CLN1 families. Our results indicate that CLN1 is not allelic with CLN3 but represents a different locus, which is not located within about 70 cM in chromosome 16.