PMID- 20430936
OWN - NLM
STAT- MEDLINE
DCOM- 20100928
LR  - 20211020
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 19
IP  - 14
DP  - 2010 Jul 15
TI  - Evaluation of loss of function as an explanation for SPG4-based hereditary 
      spastic paraplegia.
PG  - 2767-79
LID - 10.1093/hmg/ddq177 [doi]
AB  - The spectrum of mutations (missense, non-sense and splice-site) associated with 
      hereditary spastic paraplegia 4 (HSP-SPG4) (SPG4:OMIM#182601) has suggested that 
      this autosomal dominant disease results from loss of function. Because the 
      protein encoded by SPG4, termed spastin, is a microtubule-severing enzyme, a 
      loss-of-function scenario for the disease suggests that corticospinal axons 
      degenerate due to inadequate microtubule severing resulting from inactivation of 
      one spastin allele. Lending more complexity to the situation, there are two major 
      isoforms of spastin (M1 and M87) translated from two start codons. M87 is widely 
      expressed, while M1 is appreciably detected only in adult spinal cord. Here, we 
      focused on four HSP-associated mutations of the SPG4 gene located outside of the 
      AAA region essential for microtubule severing. We found that none of these 
      mutations affected the enzymatic activity or expression levels of either M1 or 
      M87. Three of the mutations resulted in dominant-negative activity of M1. 
      Surprisingly, the S44L mutation, which is asymptomatic when present 
      heterozygously, conferred dominant-negative activity, while the E112K mutation, 
      which is symptomatic when present heterozygously, did not. Clinical symptoms 
      reported for patients carrying the dominant-negative mutations L195V or 46Stop 
      are not more severe than those reported for patients carrying the 
      non-dominant-negative E112K mutation. These results indicate that there are cases 
      of HSP-SPG4 that cannot be explained by insufficient spastin microtubule-severing 
      activity.
FAU - Solowska, Joanna M
AU  - Solowska JM
AD  - Department of Neurobiology and Anatomy, Drexel University College of Medicine, 
      2900 Queen Lane, Philadelphia, PA 19129, USA.
FAU - Garbern, James Y
AU  - Garbern JY
FAU - Baas, Peter W
AU  - Baas PW
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20100429
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Protein Isoforms)
RN  - EC 3.6.1.- (Adenosine Triphosphatases)
RN  - EC 3.6.4.3 (Spastin)
RN  - EC 5.6.1.1 (SPAST protein, human)
SB  - IM
MH  - Adenosine Triphosphatases/*genetics/metabolism/*physiology
MH  - Base Sequence
MH  - Cells, Cultured
MH  - Genes, Dominant/physiology
MH  - Humans
MH  - Loss of Heterozygosity/physiology
MH  - Microtubules/genetics/metabolism
MH  - Models, Biological
MH  - Mutation/physiology
MH  - Protein Isoforms/genetics/metabolism/physiology
MH  - Protein Multimerization/genetics
MH  - Spastic Paraplegia, Hereditary/*genetics
MH  - Spastin
MH  - Transfection
PMC - PMC2893808
EDAT- 2010/05/01 06:00
MHDA- 2010/09/30 06:00
PMCR- 2011/07/15
CRDT- 2010/05/01 06:00
PHST- 2010/05/01 06:00 [entrez]
PHST- 2010/05/01 06:00 [pubmed]
PHST- 2010/09/30 06:00 [medline]
PHST- 2011/07/15 00:00 [pmc-release]
AID - ddq177 [pii]
AID - 10.1093/hmg/ddq177 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2010 Jul 15;19(14):2767-79. doi: 10.1093/hmg/ddq177. Epub 2010 Apr 
      29.