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Spectrum of SPG4 Mutations in a Large Collection of North American Families With Hereditary Spastic Paraplegia
Inge A. Meijer, BSc;
Collette K. Hand, PhD;
P. Cossette, MD, MSc;
Denise A. Figlewicz, PhD;
Guy A. Rouleau, MD, PhD
Arch Neurol. 2002;59:281-286.
ABSTRACT
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Background Hereditary spastic paraplegia (HSP) is a neurodegenerative disease characterized
by progressive spasticity and weakness of the lower limbs. The most common
form of HSP is caused by mutations in the SPG4 gene,
which codes for spastin, an adenosine triphosphatase with various cellular
activities (AAA) protein family member.
Objective To investigate a large collection of predominantly North American patients
with HSP for mutations in the spastin encoding gene, SPG4.
Methods DNA from 76 unrelated affected individuals was studied for mutations
by single-stranded conformational polymorphism analysis and direct sequencing.
Each new variant identified was then analyzed in 80 control subjects to determine
whether the variant is a common polymorphism or a rare mutation. All DNA samples
were amplified by polymerase chain reaction, followed by electrophoresis and
autoradiography.
Results We identified 8 novel mutations and 5 previously reported mutations
in 15 affected individuals. The novel mutations are 4 missense, 1 nonsense,
1 frameshift, and 2 splice mutations. Two polymorphisms (one in an affected
individual) were also identified.
Conclusions Our collection of families with HSP is different on a genetic level
from those previously described. The percentage of our families with a SPG4 mutation is 10% lower than the 40% estimate of families
with autosomal dominant HSP noted to be linked to this locus, and splice mutations
are not predominant in our collection. Interestingly, we also identified 2
recurring mutations in specific populations (R562Q and G559D), which may facilitate
the development of future spastin diagnostic testing in these populations.
INTRODUCTION
HEREDITARY SPASTIC paraplegia (HSP), also known as familial spastic
paraplegia (FSP) or Strümpell-Lorrain syndrome, comprises a heterogeneous
group of neurodegenerative disorders characterized by progressive lower limb
spasticity and weakness associated with bladder disturbance in approximately
50% of the cases.1-2 Clinically,
there are 2 types of HSP: the pure form, which is characterized exclusively
by leg spasticity often with bladder disturbance; and the complicated form,
which includes additional neurological abnormalities such as optic neuropathy,
dementia, ataxia, deafness, mental retardation, and extrapyramidal disturbance.1-2 The main neuropathological feature
is axonal degeneration of the distal ends of the longest ascending and descending
tracts. This neurodegeneration results in spasticity of the lower limbs, which
causes difficulty walking; in severe cases, the patients become wheelchair
bound.3-4 The age of onset varies
greatly, even within families, from early childhood to the mid-80s. The genetic
heterogeneity in individuals with HSP is demonstrated by the number of loci
(SPG1 through SPG17) that
have been mapped. These include 3 X-linked,5-7
9 autosomal dominant,8-16
and 5 autosomal recessive17-21
loci. Of all described families, 40% are linked to an autosomal dominant locus
known as SPG4 (MIM182601).22
The defective gene for SPG4 was cloned recently and
encodes a 616–amino acid protein named spastin. The protein is an adenosine
triphosphatase associated with various cellular activities (AAA) protein family
member with a characteristic AAA cassette in the C terminus from amino acid
342 to amino acid 599. According to computer predictions, the protein possesses
a nuclear localization signal, Walker motif A and B, an AAA minimal consensus
sequence, leucine zipper motifs, and a helix-loop-helix domain. Furthermore,
the protein shows strong homology to 2 yeast proteins (Yta6p and Sap1) and
to the mouse Skd1 protein. Recent evidence23
suggests that spastin might interact with tubulin, but its main function remains
unknown despite its homology to other proteins and functional domains. To
date, more than 50 mutations have been reported in the spastin encoding gene,
including splice-site, nonsense, missense, and frameshift mutations (insertion
and deletion), affecting either directly or indirectly the conserved AAA cassette,24-32
suggesting the functional importance of the AAA cassette. No clear genotype-phenotype
correlation has been reported, but most articles23
suggest that SPG4 is caused by the haplo-insufficiency
of spastin, which implies a critical spastin threshold.
Herein, we report 8 novel mutations and 2 novel polymorphisms identified
in the spastin encoding gene and the recurrence of 2 mutations in 2 populations,
which could be important for the development of large-scale SPG4 mutation detection efforts.
PATIENTS AND METHODS
PATIENTS
The participants included 5 control subjects and 76 unrelated patients
from families with HSP who were available in our laboratory. The families
FSP4 (Zmax= 1.09 [G. A. Rouleau, PhD, MD, unpublished data, 2000]),
FSP7 (Zmax = 2.7), and FSP28 (Zmax = 0.77)33
had previously shown suggestive linkage to the SPG4
locus. (Zmax signifies the maximum logarithm of odds score in genetic
linkage analysis.) The families were diagnosed as having either autosomal
dominant HSP (ADHSP) (49 families) or autosomal recessive HSP (11 families),
and the other 16 families are small families in which the pattern of inheritance
is unclear. All probands were seen by a neurologist, and the diagnostic criteria
were lower limb spasticity in the absence of any evidence for a structural
lesion or demyelination. Our collection of patients consists of mostly French
Canadian and other white (Canadian and US) families, with the exception of
2 Middle Eastern families. Patients and controls gave informed and written
consent. Genomic DNA from these individuals was prepared from peripheral blood
leukocytes by standard extraction methods.
MUTATION SCREENING
Single-Stranded Conformational Polymorphism Analysis
Polymerase chain reaction (PCR) primer pairs were designed from the
genomic DNA sequence of the human SPG4 gene (GenBank
accession numbers AL121655 and AL121658), as shown in Table 1.
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Table 1. Primers Designed for Amplification of All 17 Exons
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The 17 coding exons were amplified by PCR using approximately 20 ng
of genomic DNA and radiolabeled deoxyadenosine triphosphate in a total volume
of 13 µL for single-stranded conformational polymorphism (SSCP) analysis.
The reactions were performed in thermocyclers (PerkinElmer, Inc, Forest City,
Calif), starting with an initial denaturation of 5 minutes at 94°C followed
by 30 cycles of 30 seconds' denaturation, 30 seconds' annealing at the primer-specific
temperature, and 45 seconds' extension at 72°C. Electrophoresis of PCR
products was performed on 9.5% polyacrylamide (5% glycerol) and on 50% mutation
detection enhancement gels (Biowhittaker Molecular Applications, Rockland,
Me), followed by autoradiography. Samples showing altered migration patterns
were selected for further analysis.
Sequencing
Genomic DNA from selected samples was amplified in 50 µL of nonradiolabeled
PCR mix. The PCR products were purified with a gel extraction kit (QIAEX11;
QIAGEN, Mississauga, Ontario), after which the purified fragments were sequenced
using a thermosequenase phosphorus 33 cycle-sequencing kit (United States
Biochemical Corp, Cleveland, Ohio) and run on 6% polyacrylamide denaturing
gels.
Variations identified by sequencing were analyzed for cosegregation
in family members when available. All newly identified disease-associated
variations were examined for presence in 80 white controls (160 chromosomes)
by SSCP analysis.
RESULTS
One affected member from each of the 76 kindreds was screened for SPG4 mutations. Most families were too small to test for
linkage, and 3 families had shown suggestive linkage to the SPG4 locus in a previous study.33 We
identified 13 mutations and 2 polymorphisms in 16 families (Table 2). Our results show 8 novel mutations in the SPG4 gene: 1 frameshift (687delG), 2 splicing (A1538-2G and G1854-1C),
4 missense (C1321T, C1591T, G1810A, and G1801A), and 1 nonsense (G1425T) mutation
(Table 3). Five previously reported
mutations were also found in our collection. The transmission of these mutations
correlates with the clinical status of the families, except for some carrier
individuals who are asymptomatic, which could be due to age-dependent penetrance,
incomplete penetrance, or simply subtle symptoms. Interestingly, mutations
were identified in only 2 of 3 families previously linked to SPG4 (families FSP4 and FSP7). Seven of the novel mutations are in
the AAA cassette spanning exon 7 to 16.22 The
last novel mutation is a 1–base pair deletion in exon 3, which results
in a frameshift leading to a premature stop codon, truncating the protein
before the AAA cassette. This mutation was found in individual R11540 and
is one of the rare mutations occurring outside of the AAA cassette of spastin,29 and further suggests the importance of the AAA cassette
in spastin function. DNA for the rest of the family was unavailable for testing
of cosegregation. The other nonsense mutation, found in individual R12447,
creates a stop codon in the third conserved domain of the protein, which results
in a protein lacking the predicted helix-loop-helix domain and a leucine zipper
motif.
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Table 2. Clinical Information of the Probands*
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Table 3. Summary of Mutations Identified in Probands With Hereditary
Spastic Paraplegia
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This study identified 4 novel missense mutations, all occurring in the
AAA cassette. The mutation C1321T in exon 9 changes a serine (a polar and
hydrophilic amino acid) into a leucine (a hydrophobic amino acid). A mutation
in exon 12 leads to a C1591T change, where proline with a cyclic ring is substituted
by a hydrophobic linear amino acid, which occurs close to the conserved helix-loop-helix
domain. The mutation G1801A (in exon 15) gives rise to an amino acid change
from glutamic acid to the smaller aspartic acid in the conserved 6226 domain.
This mutation was found in 2 French Canadian families with HSP. Last, a missense
mutation, G1810A, in exon 15 was found in 2 white US families, and changes
a basic amino acid (arginine) to an uncharged amino acid (glutamine). The
novel missense mutations all occur in a domain or near a domain of the AAA
cassette, suggesting the importance of conserved amino acid structure in this
region. None of the variants were found in 160 control chromosomes by SSCP
analysis. There is only one report31 of a coding
polymorphism, and it is not the same as any of the previously mentioned mutations.
We found 2 new splice-site mutations (A1538-2G and G1854-1C) in the
acceptor splice site of exons 11 and 15, respectively.34
For both mutations, the predicted truncated protein lacks a part of the AAA
cassette, which probably renders the protein nonfunctional and causes disease.
Another possibility is that the splicing machinery uses an alternative cryptic
splice acceptor, which results in a defective protein.
We also detected 2 possible polymorphisms (G1417A and G1619 + 16T).
One polymorphism leads to an amino acid change (R431Q) in the third conserved
domain of spastin of a spouse of an affected individual included in the screening
as a control. This individual was seen by a neurologist and was not affected
with HSP. The proband of this family is individual R12320, who has a missense
mutation (G1801A). The other polymorphism is an intronic substitution 16 nucleotides
away from the exon in an affected individual and does not show cosegregation
in the family.
COMMENT
Fifteen mutations, 8 that are novel, were identified in the SPG4 gene of patients from a collection of 76 predominantly North American
families with HSP. Interestingly, mutations in the spastin encoding gene were
found in only 15 (31%) of the 49 known families with ADHSP who were analyzed,
which suggests that our collection of families represents a subpopulation
that does not exactly conform to the 40% estimate of families with ADHSP linked
to SPG4. A previous report33
of linkage analysis from our laboratory showed that only 14% of the families
in that study33 linked to SPG4, which correlates with the lower percentage of mutations found
in the screening. Some of the 16 small families with an unclear pattern of
inheritance could also be families with ADHSP, which would decrease the percentage
of our families linked to SPG4. Furthermore, 11 families
with recessive disease were included in the screening because Lindsey and
colleagues27 reported a homozygous mutation
in spastin, S44L, in a kindred with autosomal recessive HSP. There were no
mutations detected in any of our families with recessive disease. These data
suggest that SPG4 mutations may be responsible for
a smaller fraction of ADHSP than previously reported, and that spastin gene
screening is only worthwhile in kindreds showing clear autosomal dominant
inheritance. However, it is possible that our screening underestimated the
fraction of SPG4 mutation–positive families
because SSCP analysis is only 80% to 100% effective in detecting mutations,35 and mutations occurring in the noncoding regions,
such as the promotor and other regulatory sequences, would not be detected
by our screening, which analyzed the exons and the intron-exon junctions.
Nevertheless, our methods are similar to those used in other SPG4 mutation screenings.
While most reports of SPG4 mutations show a
predominance of splice mutations, missense mutations were the most frequent
ones found in our study. Only 3 splice mutations were found of 13 mutations
identified in affected individuals. This could be related to the fact that
our families are North American, and, to our knowledge, no large-scale study
has ever been performed on this population. We do not think it is likely that
variants in the splice junction were not detected because the primers used
in this study included approximately 30 base pairs of the flanking intronic
regions. The missense mutations found in affected individuals were not found
in 160 control chromosomes, and showed cosegregation with the disease phenotype
in the respective families. All affected individuals in a SPG4 mutation–positive family had the identified mutation. Because
HSP has incomplete and age-dependent penetrance, some seemingly unaffected
individuals (Fam33, R7050, and some family members tested for cosegregation)
in our screening carried a mutation in the spastin encoding gene. In addition,
it is estimated that 25% of individuals are asymptomatic or unaware of their
symptoms.36 These data strongly support a causative
role for these mutations in individuals with HSP.
The spastin gene is highly conserved through species, which suggests
that amino acid changes, especially when present in the AAA cassette, are
likely to have a consequence on protein function. There are no reports of
a polymorphism in the coding region in this gene except for one variant, G1004A,31 which was first detected in a proband of a family
with HSP but not in 80 controls. Our study identified the same variant in
a second affected individual. Unfortunately, no other affected individuals
in this kindred are available for testing, but the variant was not present
in 80 controls. Because this variant has not been detected in 320 control
chromosomes and has twice been identified in affected individuals, it is likely
that the variant is a mutation involved in disease etiology. The variant,
which does not change the amino acid sequence, could possibly disrupt an exonic
splicing enhancer or silencer, thereby affecting the patterns or efficiency
of messenger RNA (mRNA) splicing.37 Future
mRNA work is required to further investigate the effects of this mutation.
Two polymorphisms, one of which leads to an amino acid substitution, were
also identified in this study. The characterization of variants as polymorphisms
should be confirmed by mRNA reverse transcriptase–PCR analysis and studies
of larger control populations.
Five mutations were identified in individuals with complicated HSP showing
atypical symptoms, such as restless legs, atypical seizures, and dysarthria.
One interesting individual (aged 45 years) has a nonsense mutation in exon
10, with severe manifestation of disease showing spasticity, footdrop, and
signs of ataxia, dysarthria, and nystagmus. The severe phenotype could be
classified as complicated HSP or spastic ataxia and suggests that this gene
might also be involved in other clinical entities. Contrary to the nonsense
mutation previously mentioned, a conservative mutation in exon 10 for patient
R5913 (aged 66 years) caused early-onset progressive spasticity, rendering
the patient bedridden, with rather uncommon fecal incontinence (Table 2). Last, there are 2 patients (R7050 and Fam33) who have
no mobility problems and were unaware that they are affected. They have a
previously reported splice mutation31 and a
nonsense mutation, respectively. One would expect that the individual with
the nonsense mutation in exon 15 and, therefore, lacking the C-terminal end
of the AAA cassette, might have a relatively severe phenotype, but remarkably
that is not the case. The fact that a splice alteration in acceptor exon 15
causes disease suggests that the C-terminal part of the AAA cassette is important
for function and that having even a part of the cassette is not sufficient
for normal function. More in-depth phenotype-genotype correlation studies
would be necessary to further support that there is no actual correlation.
In addition, patients R9259 and R12320 have the same mutation but different
phenotypes, particularly age of onset. The clinical variability that occurs
in individuals with the same or similar mutations might be due to modifier
genes; this hypothesis is supported by a report38
of mutations found in the EAAT2 gene (already involved
in amyotrophic lateral sclerosis) in some patients with HSP. The modifier
gene theory can also partly explain why there are reports of complicated HSP
and pure HSP at the SPG4 locus. The hypothetical
modifier might be related to the conserved AAA cassette. Spastin bound to
adenosine triphosphate could bind a modifier or activate a secondary gene,
which allows for greater expressivity of the phenotype. Unfortunately, the
function of spastin can only be hypothesized.
To our knowledge, this study is the first to identify 2 recurring mutations.
The G1801A mutation was identified in 2 seemingly unrelated French Canadian
families, and the G1810A mutation was found in 2 seemingly unrelated white
US families. This suggests that these 2 mutations show a higher frequency
in the specific populations, which could be helpful for future SPG4 diagnostic testing in these populations. It is important to identify
frequent mutations in specific populations because the spectrum for spastin
gene mutations is so great, making efficient genetic testing only feasible
in subpopulations. There were 24 other French Canadian families included in
the screening who did not show any significant variation in the SPG4 gene. These families are not all from the same region in Quebec,
but are assumed to belong to the general French Canadian population. The results
suggest that there is at least one more defective gene responsible for HSP
in the French Canadian population.
In conclusion, this report presents 8 novel mutations in the SPG4 gene, contributing to the large spectrum of mutations found in
this gene. Continuing to identify new mutations is important, particularly
for developing diagnostic testing programs based on the frequency of mutations
in specific populations. Further phenotype-genotype correlations studies are
required to unveil the reason behind the great variable expressivity for the SPG4 form. A better understanding of the function of spastin
is vital to discovering a treatment for HSP, and future phenotype-genotype
studies and localization studies for the protein will be necessary.
AUTHOR INFORMATION
Accepted for publication September 24, 2001.
Author contributions: Study concept and design (Ms Meijer and Drs Hand, Figlewicz, and Rouleau); acquisition
of data (Ms Meijer, and Drs Cossette, Figlewicz, and Rouleau); analysis and interpretation of data (Ms Meijer and
Drs Hand and Cossette); drafting of the manuscript (Ms Meijer and Dr Hand); critical revision of the manuscript for important
intellectual content (Ms Meijer and Drs Hand, Cossette,
Figlewicz, and Rouleau); obtained funding (Dr Rouleau); administrative, technical, and material support (Ms Meijer and Drs Hand, Cossette, Figlewicz, and Rouleau); and study
supervision (Drs Hand, Cossette, Figlewicz, and Rouleau).
This study was supported by the Muscular Dystrophy Association, Tucson,
Ariz; and the Canadian Institute of Health Research, Ottawa, Ontario (Dr Rouleau).
We thank all the families with HSP (and their referring physicians)
who participated in this study; and André Toulouse, MSc, PhD, for carefully
reading the manuscript.
Corresponding author: Guy A. Rouleau, MD, PhD, Centre for Research
in Neuroscience, The Montreal General Hospital Research Institute, 1650 Cedar
Ave, Room L7-224, Montreal, Quebec, Canada H3G 1A4 (e-mail: mi32{at}musica.mcgill.ca).
From the Centre for Research in Neuroscience, McGill University, The
Montreal General Hospital Research Institute, Montreal, Quebec (Ms Meijer,
and Drs Hand, Cossette, and Rouleau); and the Department of Neurology, University
of Rochester Medical Center, Rochester, NY (Dr Figlewicz).
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Hum Mol Genet 2006;15:3544-3558.
ABSTRACT
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High frequency of partial SPAST deletions in autosomal dominant hereditary spastic paraplegia
Beetz et al.
Neurology 2006;67:1926-1930.
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Clinical features of hereditary spastic paraplegia due to spastin mutation.
McDermott et al.
Neurology 2006;67:45-51.
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Eight Novel Mutations in SPG4 in a Large Sample of Patients With Hereditary Spastic Paraplegia.
Crippa et al.
Arch Neurol 2006;63:750-755.
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Spastin mutations are frequent in sporadic spastic paraparesis and their spectrum is different from that observed in familial cases
Depienne et al.
J. Med. Genet. 2006;43:259-265.
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Spastin and atlastin, two proteins mutated in autosomal-dominant hereditary spastic paraplegia, are binding partners
Sanderson et al.
Hum Mol Genet 2006;15:307-318.
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Early-onset ALS with long-term survival associated with spastin gene mutation
Meyer et al.
Neurology 2005;65:141-143.
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A new SPG4 mutation in a variant form of spastic paraplegia with congenital arachnoid cysts
Orlacchio et al.
Neurology 2004;62:1875-1878.
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Three Novel Mutations of the Spastin Gene in Chinese Patients With Hereditary Spastic Paraplegia
Tang et al.
Arch Neurol 2004;61:49-55.
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Subtle Cognitive Impairment but No Dementia in Patients With Spastin Mutations
Tallaksen et al.
Arch Neurol 2003;60:1113-1118.
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Science in motion: common molecular pathological themes emerge in the hereditary spastic paraplegias
Reid
J. Med. Genet. 2003;40:81-86.
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Mutations of SPG4 are responsible for a loss of function of spastin, an abundant neuronal protein localized in the nucleus
Charvin et al.
Hum Mol Genet 2003;12:71-78.
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