Neurogenetics

, Volume 7, Issue 2, pp 131–132 | Cite as

A founder effect and mutational hot spots may contribute to the most frequent mutations in the SPG3A gene

  • Michito Namekawa
  • Isabelle Nelson
  • Pascale Ribai
  • Alexandra Dürr
  • Elodie Denis
  • Giovanni Stevanin
  • Merle Ruberg
  • Alexis Brice
Letter to the Editors

Sirs,

SPG3A is the most frequent very early-onset hereditary spastic paraplegia (HSP) [1]. In the 12 studies of SPG3A mutations performed so far, 21 different mutations were found in a total of 40 families. All were missense mutations, except for one insertion. Most SPG3A mutations reported so far have been unique. Two mutations were strikingly frequent, however, in our previous clinico-genetic study and in studies by others: c.715C>T (R239C, 10 families; 25%) and c.1483C>T (R495W, 6 families; 15%) (reviewed in [1]). The unusual frequency of these two mutations raises the question as to whether they have arisen de novo, suggesting the existence of mutational hot spots, or whether they are due to a common founder.

To determine whether common founders explain the frequency of these mutations, we have analyzed the associated haplotypes in three families with the c.715C>T (R239C) mutation (FSP-092, FSP-566, and FSP-590) and four families with the c.1483C>T (R495W) mutation (FSP-034, FSP-132, FSP-484, and FSP-634), all of which were whites of French origin [1, 2]. Blood samples were obtained with written informed consent from the patients and their relatives. Linkage disequilibrium with seven flanking microsatellite markers (D14S984, AFMa086yh5, D14S58, D14S1031, D14S978, D14S1018, and D14S589; GDB Human Genome Database [Database online]), spanning 2.85cM, and two polymorphisms in the SPG3A gene (c.84A>G in Exon 2 and c.183G>A in Exon3) [2] was examined, as described [3].

The disease-segregating haplotypes are shown in Table 1. When the phase of transmission could not be determined, both alleles are indicated. The three families with the R239C mutations had different alleles for most of the markers, suggesting that the mutations arose independently. The R495W mutation was found on at least two different haplotypes, demonstrating that it can also occur by independent mutational events. Three of the four families with R495W mutations, however, shared not only the frequent intragenic and centromeric markers but also the less frequent allele of the telomeric marker D14S978 (allele 228, 7%), suggesting a possible founder effect, but given the frequency of most of the linked alleles, recurrent mutations on an at-risk haplotype cannot be excluded.
Table 1

Haplotypes associated with R239C and R495W mutations in SPG3A gene

Markers

R239C

R495W

Frequency of the putative R495W founder allelea

Family code

FSP-092

FSP-566

FSP-590

FSP-034

FSP-132

FSP-484

FSP-634

 

D14S984

219

211

241

243

219

219

211/219

0.48

AFMa086yh5

271

275/279

275

275

275

275

275

0.87b

D14S58

197/199

199

195

207

195/197

197

195/197

0.37b

D14S1031

236/238

236

236

222

236

236

236

0.54b

SPG3A

Ex2

A

A

G

A

A

A

A

0.92b

Ex3

A

A

A

A

A

A

A

0.70b

D14S978

254

246

256

230/252

228

228

228/256

0.07

D14S1018

211

211

204/207

207

204/207

207

204/207

0.41

D14S589

139

139/166

166

139

139

139

139

0.72b

Data set in bold indicate putative founder alleles

aThe frequencies of the alleles are cited from the GDB Human Genome Database (http://gdbwww.gdb.org)

bThe frequencies of the alleles are cited from our original data

Both mutations affect cytosines in CpG dinucleotides. Since 5-methyl cytosines in CpG dinucleotides are prone to mutate unidirectionally to thymines by spontaneous deamination, and the \( \underline{\underline {\text{C}}} {\text{G - to - }}\underline{\underline {\text{T}}} {\text{G or C}}\underline{\underline {\text{G}}} {\text{ - to - C}}\underline{\underline {\text{A}}} \) transitions are the most important cause of point mutations in humans, representing 23% of all single-base-pair changes [4], we used the bisulfite conversion method [5] to determine whether c.715C and c.1483C were methylated. This was indeed the case (see Supplemental material).

These results demonstrate that the most common mutation in the SPG3A gene c.715C>T (R239C) did not result from a founder effect in the families that we studied, but occurred in a mutational hot spot defined by a methylated CpG dinucleotide. The second most frequent mutation c.1483C>T (R495W) can be attributed both to a common founder in some families, but also to independent mutational events, again on a methylated CpG dinucleotide. Our findings demonstrate that SPG3A mutations can occur de novo in offspring of normal parents. Genetic testing of sporadic patients with very early-onset pure spastic paraplegia for the two frequent point mutations in this gene is, therefore, recommended.

Notes

Acknowledgements

We are grateful to all the patients and their families for participating. The DNA and Cell Bank of IFR70 is acknowledged for the preparation of the DNA samples. This study was supported by grants from the French National Institute for Health and Medical Research, the VERUM foundation (A.B.), the GIS/Rare Diseases Institute (A02191DS-SPATAX; A.D.), Lilly (Japan; M.N.), the French Foreign Ministry (M.N.), la Fondation Recherche Médicale (M.N.), Collège de Médecine des Hôpitaux de Paris (P.R.), and European Neurological Society (P.R.).

The experiments performed comply with current legislation in France.

Supplementary material

10048_2006_28_MOESM1_ESM.pdf (389 kb)
Supplement 1c.715C and c.1483C which are frequently mutated in SPG3A are methylated: results of a bisulfite analysis (PDF 397 kb)

References

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Copyright information

© Springer-Verlag 2006 2006

Authors and Affiliations

  • Michito Namekawa
    • 1
  • Isabelle Nelson
    • 1
  • Pascale Ribai
    • 1
    • 2
  • Alexandra Dürr
    • 1
    • 2
  • Elodie Denis
    • 1
  • Giovanni Stevanin
    • 1
    • 2
  • Merle Ruberg
    • 1
  • Alexis Brice
    • 1
    • 2
    • 3
    • 4
    • 5
  1. 1.INSERM U679 (former U289), Federative Institute for Neuroscience Research (IFR70)Salpêtrière HospitalParisFrance
  2. 2.Department of Genetics Cytogenetics and Embryology, AP-HPSalpêtrière HospitalParisFrance
  3. 3.Federation of Neurology, AP-HPSalpêtrière HospitalParisFrance
  4. 4.Salpêtrière Medical SchoolPierre and Marie Curie UniversityParisFrance
  5. 5.INSERM U679 (former 289)Hôpital de la SalpêtrièreParis Cedex 13France

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