Defective mitochondrial mRNA maturation is associated with spastic ataxia.

In human mitochondria, polyadenylation of mRNA, undertaken by the nuclear-encoded mitochondrial poly(A) RNA polymerase, is essential for maintaining mitochondrial gene expression. Our molecular investigation of an autosomal-recessive spastic ataxia with optic atrophy, present among the Old Order Amish, identified a mutation of MTPAP associated with the disease phenotype. When subjected to poly(A) tail-length assays, mitochondrial mRNAs from affected individuals were shown to have severely truncated poly(A) tails. Although defective mitochondrial DNA maintenance underlies a well-described group of clinical disorders, our findings reveal a defect of mitochondrial mRNA maturation associated with human disease and imply that this disease mechanism should be considered in other complex neurodegenerative disorders.

Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.

Distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (OMIM #182960) is a heterogeneous group of disorders characterized by an almost exclusive degeneration of motor nerve fibers, predominantly in the distal part of the limbs. Silver syndrome (OMIM #270685) is a rare form of hereditary spastic paraparesis mapped to chromosome 11q12-q14 (SPG17) in which spasticity of the legs is accompanied by amyotrophy of the hands and occasionally also the lower limbs. Silver syndrome and most forms of dHMN are autosomal dominantly inherited with incomplete penetrance and a broad variability in clinical expression. A genome-wide scan in an Austrian family with dHMN-V (ref. 4) showed linkage to the locus SPG17, which was confirmed in 16 additional families with a phenotype characteristic of dHMN or Silver syndrome. After refining the critical region to 1 Mb, we sequenced the gene Berardinelli-Seip congenital lipodystrophy (BSCL2) and identified two heterozygous missense mutations resulting in the amino acid substitutions N88S and S90L. Null mutations in BSCL2, which encodes the protein seipin, were previously shown to be associated with autosomal recessive Berardinelli-Seip congenital lipodystrophy (OMIM #269700). We show that seipin is an integral membrane protein of the endoplasmic reticulum (ER). The amino acid substitutions N88S and S90L affect glycosylation of seipin and result in aggregate formation leading to neurodegeneration.

A clinical, genetic and candidate gene study of Silver syndrome, a complicated form of hereditary spastic paraplegia.

Silver syndrome (SS) is a complicated form of hereditary spastic paraplegia associated with distal wasting of the small muscles of the hands. We have previously described a large kindred with SS and mapped a genetic locus (SPG17) to chromosome 11q12-q14. In the current study we analyse the clinical phenotype and perform linkage analysis in three new SS families. In addition we analyse candidate genes mapping to the SS locus (SPG17). Clinical assessments were performed on 25 (15 affected) individuals from each family in which SS segregates with variable clinical expression. Neurophysiological studies, performed in the index case of two families, suggested anterior horn cell or nerve root involvement. Linkage analysis using microsatellite markers mapping to the SPG17 locus was performed and only one of the three families had a microsatellite segregation pattern compatible with linkage. Candidate genes mapping to the SS critical region were analysed in this and one other SPG17-linked family. Mutation analysis of genes encoding calpain 1 ( CAPN1), copper chaperone for superoxide dismutase ( CCS), ADP ribosylation factor-like 2 ( ARL2), LOC120664, a putative homologue of atlastin ( ATLSTL-1) and sorting nexin 15 ( SNX15) failed to identify any disease-specific mutations. SS therefore exhibits both clinical and genetic heterogeneity and the SPG17 locus may account for a significant proportion of SS mutations in the UK.

A novel NIPA1 mutation associated with a pure form of autosomal dominant hereditary spastic paraplegia.

The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterised by lower limb spasticity and weakness. Mutations in NIPA1 (Nonimprinted in Prader-Willi/Angelman syndrome 1) have recently been identified as a cause of autosomal dominant pure HSP, with one mutation described in two unrelated families. NIPA1 has no known function but is predicted to possess nine transmembrane domains and may function as a receptor or transporter. Here we present a large British pedigree in which linkage analysis conclusively demonstrates linkage to the NIPA1 locus (maximum multipoint LOD score 4.6). Subsequent mutation analysis identified a novel missense substitution in a highly conserved NIPA1 residue (G106R) which further confirms a causative link between NIPA1 mutation and autosomal dominant hereditary spastic paraplegia.