Type 2 diabetes: Evidence for linkage on chromosome 20 in 716 Finnish affected sib pairs

We are conducting a genome scan at an average resolution of 10 centimorgans (cM) for type 2 diabetes susceptibility genes in 716 affected sib pairs from 477 Finnish families. To date, our best evidence for linkage is on chromosome 20 with potentially separable peaks located on both the long and short arms. The unweighted multipoint maximum logarithm of odds score (MLS) was 3.08 on 20p (location, x̂ = 19.5 cM) under an additive model, whereas the weighted MLS was 2.06 on 20q (x̂ = 57 cM, recurrence risk, λ̂s = 1.25, P = 0.009). Weighted logarithm of odds scores of 2.00 (x̂ = 69.5 cM, P = 0.010) and 1.92 (x̂ = 18.5 cM, P = 0.013) were also observed. Ordered subset analyses based on sibships with extreme mean values of diabetes-related quantitative traits yielded sets of families who contributed disproportionately to the peaks. Two-hour glucose levels in offspring of diabetic individuals gave a MLS of 2.12 (P = 0.0018) at 9.5 cM. Evidence from this and other studies suggests at least two diabetes-susceptibility genes on chromosome 20. We have also screened the gene for maturity-onset diabetes of the young 1, hepatic nuclear factor 4-a (HNF-4α) in 64 affected sibships with evidence for high chromosomal sharing at its location on chromosome 20q. We found no evidence that sequence changes in this gene accounted for the linkage results we observed.

Elucidating the mechanism of familial amyloidosis– Finnish type: NMR studies of human gelsolin domain 2

Familial amyloidosis–Finnish type (FAF) results from a single mutation at residue 187 (D187N or D187Y) within domain 2 of the actin-regulating protein gelsolin. The mutation somehow allows a masked cleavage site to be exposed, leading to the first step in the formation of an amyloidogenic fragment. We have performed NMR experiments investigating structural and dynamic changes between wild-type (WT) and D187N gelsolin domain 2 (D2). On mutation, no significant structural or dynamic changes occur at or near the cleavage site. Areas in conformational exchange are observed between β-strand 4 and α-helix 1 and within the loop region following β-strand 5. Chemical shift differences are noted along the face of α-helix 1 that packs onto the β-sheet, suggesting an altered conformation. Conformational changes within these areas can have an effect on actin binding and may explain why D187N gelsolin is inactive. {1H-15N} nuclear Overhauser effect and chemical shift data suggest that the C-terminal tail of D187N gelsolin D2 is less structured than WT by up to six residues. In the crystal structure of equine gelsolin, the C-terminal tail of D2 lies across a large cleft between domains 1 and 2 where the masked cleavage site sits. We propose that the D187N mutation destabilizes the C-terminal tail of D2 resulting in a more exposed cleavage site leading to the first proteolysis step in the formation of the amyloidogenic fragment.

Destabilization of Ca2+-free gelsolin may not be responsible for proteolysis in Familial Amyloidosis of Finnish Type

Mutations at position 187 in secreted gelsolin enable aberrant proteolysis at the 172–173 and 243–244 amide bonds, affording the 71-residue amyloidogenic peptide deposited in Familial Amyloidosis of Finnish Type (FAF). Thermodynamic comparisons of two different domain 2 constructs were carried out to study possible effects of the mutations on proteolytic susceptibility. In the construct we consider to be most representative of domain 2 in the context of the full-length protein (134–266), the D187N FAF variant is slightly destabilized relative to wild type (WT) under the conditions of urea denaturation, but exhibits a Tm identical to WT. The D187Y variant is less stable to intermediate urea concentrations and exhibits a Tm that is estimated to be ≈5°C lower than WT (pH 7.4, Ca2+-free). Although the thermodynamic data indicate that the FAF mutations may slightly destabilize domain 2, these changes are probably not sufficient to shift the native to denatured state equilibrium enough to enable the proteolysis leading to FAF. Biophysical data indicate that these two FAF variants may have different native state structures and possibly different pathways of amyloidosis.

Paternal and maternal DNA lineages reveal a bottleneck in the founding of the Finnish population.

An analysis of Y-chromosomal haplotypes in several European populations reveals an almost monomorphic pattern in the Finns, whereas Y-chromosomal diversity is significantly higher in other populations. Furthermore, analyses of nucleotide positions in the mitochondrial control region that evolve slowly show a decrease in genetic diversity in Finns. Thus, relatively few men and women have contributed the genetic lineages that today survive in the Finnish population. This is likely to have caused the so-called "Finnish disease heritage"-i.e., the occurrence of several genetic diseases in the Finnish population that are rare elsewhere. A preliminary analysis of the mitochondrial mutations that have accumulated subsequent to the bottleneck suggests that it occurred about 4000 years ago, presumably when populations using agriculture and animal husbandry arrived in Finland.