Indentifying gene of silver syndrome by verification of mutations


Applicants :
Team in Graz: Institute of Medical Biology and Human Genetics : Christian Windpassinger und Dr. Michaela Auer- Grumbach.

The hereditary spastic parapareses (HSP) are a clinically and genetically heterogeneus group of disorders characterised by progressive lower limb spasticity and weakness. They may be complicated by additional neurological and non-neurological features. Silver syndrome is an autosomal dominant inherited distinct variant of HSP with reduced penetrance and broad phenotypic variation of the disease. Patients often have prominent weakness and wasting of the small hand and sometimes foot muscles as well as foot deformity in addition to spasticity of the lower limbs and gait disturbance.

We ascertained a large Austrian family of 12 generations, in which > 50 affected individuals showed mild to moderate spasticity of the lower limbs, foot deformity and / or mild to severe amyotrophy predominantly of the small hand muscles but normal sensation. Due to prominent hand muscle involvement one branch of the family was previously diagnosed as distal hereditary motor neuronopathy type V. Other family members were afflicted with spasticity of the lower limbs which occured in isolation or was accompanied by wasting of the small hand muscles and / or a peripheral motor neuropathy. A genome wide scan was performed and significant linkage to chromosome 11q12-q14 could be demonstrated. This gene locus overlaps with the locus recently described in an English family with Silver syndrome. The critical region on the long arm of chromosome 11 has been considerably reduced by haplotype analysis of our large family. We also started to characterize and annotate the genomic region and we have already excluded several functional and positional candidate genes by DNA-sequencing.

The main goal of this research project is to narrow down the critical region by haplotype analysis and recombination events in the family. By direct sequencing of genes located within this region we will try to identify the gene responsible for Silver syndrome by mutation analysis. The identification of this gene will have a major impact on the understanding of novel disease mechanisms and underlying cellular processes responsible for HSP and other motor neuron disorders.

 

Dr. Auer- Grumbach; Christian Windpassinger