A M Dearlove

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.

Localization of a Gene for Familial Hemophagocytic Lymphohistiocytosis at Chromosome 9q21.3-22 by Homozygosity Mapping

Familial hemophagocytic lymphohistiocytosis (FHL), also known as familial erythrophagocytic lymphohistiocytosis and familial histiocytic reticulosis, is a rare autosomal recessive disorder of early childhood characterized by excessive immune activation. Linkage of the disease gene to an approximately 7.8-cM region between markers D9S1867 and D9S1790 at 9q21.3-22 was identified by homozygosity mapping in four inbred FHL families of Pakistani descent with a combined maximum multipoint LOD score of 6.05. This is the first genetic locus to be described in FHL. However, homozygosity by descent across this interval could not be demonstrated in an additional affected kindred of Arab origin, whose maximum multipoint LOD score was -0.12. The combined sample revealed significant evidence for linkage to 9q markers (LOD score with heterogeneity, 5.00). Identification of the gene(s) involved in the pathogenesis of FHL will contribute to an understanding of the control of T-lymphocyte and macrophage activation, which is central to homeostasis in the immune system.

CTLA-4/CD28 gene region is associated with genetic susceptibility to coeliac disease in UK families

Coeliac disease (CD) is a malabsorption disorder characterised by a small intestinal enteropathy that reverts to normal on removal of dietary gluten. Susceptibility to disease has a strong genetic component. Ninety percent of patients in northern Europe have the HLA class II alleles DQA1*0501 and DQB1*0201, which encode the cell surface molecule HLA-DQ2.1 However, haplotype sharing probabilities across the HLA region in affected sib pairs suggest that genes within the MHC complex contribute no more than 40% of the sib familial risk of CD, making the non-HLA linked gene (or genes) the stronger determinant.2 Attempts have been made to identify these loci using genome wide linkage studies. Zhong et al 3 performed an autosomal screen in 45 affected sib pairs from the west coast of Ireland, using 328 microsatellite markers. They found evidence of linkage with lod scores of greater than 2.0 in five areas: 6p23 (separate from HLA), 7q31.3, 11p11, 15q26, and 22cen. A larger genome wide search involving 110 affected Italian sib pairs using 281 markers found no evidence of linkage in these five areas.4 It did, however, propose a novel susceptibility locus at 5qter, important in both symptomatic and silent CD, and another at 11qter, which appeared to differentiate the two forms. In UK families an initial genome wide search,5 followed by a study of 17 candidate regions6 identified five areas with lod scores of greater than 2.0: 6p12, 11p11, 17q12, 18q23, and 22q13. Of these, 11p11 replicates one of the loci identified by Zhong et al 3 and it is likely that this area contains an important non-HLA susceptibility locus. However, in general the results of these studies are disappointingly inconsistent. A number of candidate genes have been investigated in linkage and association studies. Of these, the only region with repeatedly …

Autosomal dominant spastic paraplegia: refined SPG8 locus and additional genetic heterogeneity.

Objective: To map the gene responsible for autosomal dominant pure hereditary spastic paraplegia (ADPHSP) in a large affected family. Background: Autosomal dominant pure hereditary spastic paraplegia (ADPHSP) is genetically heterogeneous, and loci have been mapped at chromosomes 2p (SPG4), 14q (SPG3), 15q (SPG6), and recently, in a single family, at chromosome 8q24 (SPG8). Methods: The authors carried out a genomewide linkage screen on a large family with ADPHSP, for which linkage to the chromosome 2, 14, and 15 loci was excluded. Results: Analysis of markers on chromosome 8q24 gave a peak two-point lod score of 4.49 at marker D8S1799. Analysis of recombination events in this family and in the previously published SPG8-linked family narrowed the SPG8 locus from 6.2 cM to a 3.4-cM region between markers D8S1804 and D8S1179. In another four families, linkage to all four known ADPHSP loci was excluded. The SPG8-linked family had a significantly older mean age at onset of symptoms and had significantly more wheelchair-using patients than the four linkage-excluded families. Conclusions: These results contain the presence of an autosomal dominant pure hereditary spastic paraplegia (ADPHSP) locus at chromosome 8q24 and strongly suggest that there are at least five ADPHSP loci. The data provide additional evidence for locus–phenotype correlations in ADPHSP.

Benign familial infantile convulsions: report of a UK family and confirmation of genetic heterogeneity.

Editor—Benign familial infantile convulsions (BFIC) (OMIM 601764) is a recently recognised idiopathic epilepsy syndrome originally described in families of Japanese ancestry and more recently in Italian families.1-3 It has since been reported in France, Singapore, Sweden, Germany, USA, and Argentina,4-7 but to our knowledge never in the United Kingdom. The onset of seizures in BFIC is between 3 and 12 months old, and they are mostly of a partial type, some with secondary generalisation. These seizures tend to occur in clusters over several days and remit spontaneously at about 18 months. Ictal electroencephalograms (EEG) show diffuse discharge from the centro-occipital region, although the interictal EEG is normal. The course of the disease is benign with ultimately normal psychomotor development. There is considerable evidence that genetic factors are involved in the human epilepsies, although these genetic factors are complex and incompletely understood. One approach to understanding the molecular pathological basis of seizure disorders is to identify the genes involved in defined familial epilepsy syndromes. To date, genes for four autosomal dominant epileptic diseases have been mapped or cloned: benign familial neonatal convulsions at chromosomes 20q13 ( EBN1 ) and 8q24 ( EBN2 ), partial epilepsy with auditory symptoms at chromosome 10q ( EPT ), autosomal dominant nocturnal frontal lobe epilepsy at chromosome 20q13 ( CHRNA4 ), and BFIC at chromosome 19q in five Italian families.6 8 Haplotype mapping suggests that the BFIC locus at 19q is likely to lie in an approximately 6 cM region between D19S49 and D19S251.6This locus has been excluded in a single large Italian BFIC family, strongly suggesting that the condition is genetically heterogeneous.9 We present a family of United Kingdom origin with BFIC. In total, five family members were affected by a seizure disorder. The proband (case III.1, fig 1) was a male child, aged 3 …