2 HSP Research abstracts--link to free full article

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Research about the function of the protein (Atlastin)

created by the SPG3A gene.

Although somewhat unintelligible (to me), this

abstract shows that scientists at the US National

Institutes of Health (NIH) are making progress

determining the function of the Atlastin protein

created by SPG3A gene that causes a juvenile onset

version of HSP.

Once scientists understand the function of the

protein, including how a misformed version of the

protein causes HSP, the next step will be finding the

cure.

Mark Weber

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Cellular Localization, Oligomerization, and Membrane

Association of the Hereditary Spastic Paraplegia 3A

(SPG3A) Protein Atlastin

Peng-Peng Zhu, , Brigitte Lavoie,

Stadler, Marwa Shoeb, Rakesh Patel, and Craig

Blackstone

Cellular Neurology Unit, NINDS, National Institutes of

Health, Bethesda, MD 20892-4164

Corresponding Author: blackstc@...

Hereditary spastic paraplegias (HSPs) comprise a group

of clinically heterogeneous syndromes characterized by

lower extremity spasticity and weakness, with distal

axonal degeneration in the long ascending and

descending tracts of the spinal cord. The early-onset

HSP SPG3A is caused by mutations in the atlastin/hGBP3

gene (renamed here atlastin1), which codes for a

64-kDa member of the dynamin/Mx/guanylate-binding

protein (GBP) superfamily of large GTPases. The

atlastin1 protein is localized predominantly in brain,

where it is enriched in pyramidal neurons in the

cerebral cortex and hippocampus. In cultured cortical

neurons, atlastin1 co-localizes most prominently with

markers of the Golgi apparatus, and immunogold

electron microscopy reveals a predominant localization

of atlastin1 to the cis-Golgi. Yeast two-hybrid

analyses and co-immunoprecipitation studies

demonstrate that atlastin1 can self-associate, and

gel-exclusion chromatography and chemical

cross-linking studies indicate that atlastin1 exists

as an oligomer in vivo, most likely a tetramer.

Membrane fractionation and protease protection assays

reveal that atlastin1 is an integral membrane protein

with two predicted transmembrane domains; both the

N-terminal GTP-binding and C-terminal domains are

exposed to the cytoplasm. Together these findings

indicate that the SPG3A protein atlastin1 is a

multimeric, integral membrane GTPase that may be

involved in Golgi membrane dynamics or vesicle

trafficking.

A FREE copy of the entire article is available at

http://www.jbc.org/cgi/content/abstract/M306702200v1

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Refinement of the " Silver syndrome locus " on

chromosome 11q12-q14 in four families and exclusion of

eight candidate genes

Christian Windpassinger1, Klaus Wagner1, Erwin Petek1,

Renate Fischer2 and a Auer-Grumbach1

1 Institute of Medical Biology and Human Genetics,

Karl-Franzens University Graz, Harrachgasse 21/8, 8010

Graz, Austria

2 Department of Neurology, Karl-Franzens University,

Graz, Austria

Received: 3 June 2003 Accepted: 4 August 2003

Published online: 16 September 2003

Abstract: Silver syndrome is a rare variant of

autosomal dominant complicated hereditary spastic

paraparesis (HSP), in which spasticity of the lower

limbs is accompanied by amyotrophy of the hands and

occasionally also the lower limbs. The disease locus

has been mapped to chromosome 11q12-q14. We report

four Austrian families presenting with the typical

clinical features of Silver syndrome. Sixteen

individuals were affected upon clinical and/or

electrophysiological examination. Ten persons showed

mild to severe spasticity of the lower limbs. Wasting

of the small hand muscles was present in nine affected

family members of whom three had also gait

disturbance. Three further individuals were

asymptomatic. Electrophysiological studies showed

normal or slightly to moderately slowed motor nerve

conduction velocities, reduced amplitudes and

occasionally chronodispersion of compound motor action

potentials. In one patient, conduction block was

observed. Sensory nerve action potentials were usually

normal. Molecular genetic studies demonstrate linkage

to chromosome 11q12-q14. Haplotype analysis in

affected individuals indicates a common ancestor in

the four families. By recombination analysis in

affected individuals the Silver syndrome candidate

gene interval can be reduced from 13 to 5.9 cM and can

now be placed between the markers D11S1765 and

D11S987. By sequence analysis of affected individuals

eight functional and positional candidate genes could

be excluded. Our study confirms the existence of the

Silver syndrome locus on chromosome 11q12-q14 and

provides the first report of nerve conduction velocity

studies in Silver syndrome, which demonstrate the

presence of a peripheral predominantly motor

neuropathy.

SOURCE:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=PubMed & list_uids=1\

3680364 & dopt=Abstract