Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31.

Hereditary spastic paraplegia (HSP) comprises a group of clinically and genetically heterogeneous diseases that affect the upper motor neurons and their axonal projections. For the novel SPG31 locus on chromosome 2p12, we identified six different mutations in the receptor expression-enhancing protein 1 gene (REEP1). REEP1 mutations occurred in 6.5% of the patients with HSP in our sample, making it the third-most common HSP gene. We show that REEP1 is widely expressed and localizes to mitochondria, which underlines the importance of mitochondrial function in neurodegenerative disease.

A genome-wide linkage analysis of dementia in the Amish.

Susceptibility genes for Alzheimer's disease are proving to be highly challenging to detect and verify. Population heterogeneity may be a significant confounding factor contributing to this difficulty. To increase the power for disease susceptibility gene detection, we conducted a genome-wide genetic linkage screen using individuals from the relatively isolated, genetically homogeneous, Amish population. Our genome linkage analysis used a 407-microsatellite-marker map (average density 7 cM) to search for autosomal genes linked to dementia in five Amish families from four Midwestern U.S. counties. Our highest two-point lod score (3.01) was observed at marker D4S1548 on chromosome 4q31. Five other regions (10q22, 3q28, 11p13, 4q28, 19p13) also demonstrated suggestive linkage with markers having two-point lod scores >2.0. While two of these regions are novel (4q31 and 11p13), the other regions lie close to regions identified in previous genome scans in other populations. Our results identify regions of the genome that may harbor genes involved in a subset of dementia patients, in particular the North American Amish community.

Reduction in the minimum candidate interval in the dominant-intermediate form of Charcot-Marie-Tooth neuropathy to D19S586 to D19S432.

As part of an on-going genomic screen of unlinked Charcot-Marie-Tooth disease type 2 (CMT2) families, we identified 11 regions in the genome with lod scores > or = 1.0. One of these regions was near the recently identified CMTDI1 locus on 19q. We show evidence of linkage of DUK 1118 to this region and our data reduce the minimum candidate interval for CMTDI1 to the 9-cM interval spanned by D19S586 and D19S432. We also demonstrate that five additional CMT2 families are unlinked to 19q markers, providing further evidence of CMT2 heterogeneity.

A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10).

We have identified a missense mutation in the motor domain of the neuronal kinesin heavy chain gene KIF5A, in a family with hereditary spastic paraplegia. The mutation occurs in the family in which the SPG10 locus was originally identified, at an invariant asparagine residue that, when mutated in orthologous kinesin heavy chain motor proteins, prevents stimulation of the motor ATPase by microtubule-binding. Mutation of kinesin orthologues in various species leads to phenotypes resembling hereditary spastic paraplegia. The conventional kinesin motor powers intracellular movement of membranous organelles and other macromolecular cargo from the neuronal cell body to the distal tip of the axon. This finding suggests that the underlying pathology of SPG10 and possibly of other forms of hereditary spastic paraplegia may involve perturbation of neuronal anterograde (or retrograde) axoplasmic flow, leading to axonal degeneration, especially in the longest axons of the central nervous system.