Abstract
It has been found that CDKL5 gene mutations are responsible for early-onset epilepsy and drug resistance. We screened a population of 92 patients with classic/atypical Rett syndrome, 17 Angelman/Angelman-like patients and six idiopathic autistic patients for CDKL5 mutations and exon deletions and identified seven novel mutations: six in the Rett subset and one in an Angelman patient. This last, an insertion in exon 11, c.903-904 dupGA, p.Leu302Aspfx49X, is associated with a relatively mild clinical presentation as the patient is the only one capable of sitting and walking alone. Of the six mutations, two are de novo missense changes affecting highly conserved aminoacid residues, c.215 T>C p.Ile72Thr and c.380A>G p.His127Arg (present in a mosaic condition) found in two girls with the most severe clinical presentation, while the remaining are the splicing c.145+2 T>C and c.2376+5G>A, the c.1648C>T p.Arg550X and the MPLA-identified c.162-99del261 mutation. RNA characterisation of four mutations revealed the aberrant transcript of the missense allele (case 2) and not the stop mutation (case 3), but also allowed the splicing mutation (case 1) and the c.-162-99del261 (case 4) to be categorised as truncating. The obtained data reinforce the view that a more severe phenotype is due more to an altered protein than haploinsufficiency. Furthermore, the mutational repertoire of the CDKL5 gene is shown to be expanded by testing patients with phenotypical overlap to Rett syndrome and applying multiplex ligation-dependent probe amplification.
| Original language | English |
|---|---|
| Pages (from-to) | 241-250 |
| Number of pages | 10 |
| Journal | Neurogenetics |
| Volume | 10 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Jul 2009 |
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Keywords
- Genotype-phenotype correlation
- Mutation screening
- RNA analysis
ASJC Scopus subject areas
- Genetics(clinical)
- Cellular and Molecular Neuroscience
- Genetics
Cite this
Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes. / Russo, S.; Marchi, M.; Cogliati, F.; Bonati, M. T.; Pintaudi, M.; Veneselli, E.; Saletti, V.; Balestrini, M.; Ben-Zeev, B.; Larizza, L.
In: Neurogenetics, Vol. 10, No. 3, 07.2009, p. 241-250.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes
AU - Russo, S.
AU - Marchi, M.
AU - Cogliati, F.
AU - Bonati, M. T.
AU - Pintaudi, M.
AU - Veneselli, E.
AU - Saletti, V.
AU - Balestrini, M.
AU - Ben-Zeev, B.
AU - Larizza, L.
PY - 2009/7
Y1 - 2009/7
N2 - It has been found that CDKL5 gene mutations are responsible for early-onset epilepsy and drug resistance. We screened a population of 92 patients with classic/atypical Rett syndrome, 17 Angelman/Angelman-like patients and six idiopathic autistic patients for CDKL5 mutations and exon deletions and identified seven novel mutations: six in the Rett subset and one in an Angelman patient. This last, an insertion in exon 11, c.903-904 dupGA, p.Leu302Aspfx49X, is associated with a relatively mild clinical presentation as the patient is the only one capable of sitting and walking alone. Of the six mutations, two are de novo missense changes affecting highly conserved aminoacid residues, c.215 T>C p.Ile72Thr and c.380A>G p.His127Arg (present in a mosaic condition) found in two girls with the most severe clinical presentation, while the remaining are the splicing c.145+2 T>C and c.2376+5G>A, the c.1648C>T p.Arg550X and the MPLA-identified c.162-99del261 mutation. RNA characterisation of four mutations revealed the aberrant transcript of the missense allele (case 2) and not the stop mutation (case 3), but also allowed the splicing mutation (case 1) and the c.-162-99del261 (case 4) to be categorised as truncating. The obtained data reinforce the view that a more severe phenotype is due more to an altered protein than haploinsufficiency. Furthermore, the mutational repertoire of the CDKL5 gene is shown to be expanded by testing patients with phenotypical overlap to Rett syndrome and applying multiplex ligation-dependent probe amplification.
AB - It has been found that CDKL5 gene mutations are responsible for early-onset epilepsy and drug resistance. We screened a population of 92 patients with classic/atypical Rett syndrome, 17 Angelman/Angelman-like patients and six idiopathic autistic patients for CDKL5 mutations and exon deletions and identified seven novel mutations: six in the Rett subset and one in an Angelman patient. This last, an insertion in exon 11, c.903-904 dupGA, p.Leu302Aspfx49X, is associated with a relatively mild clinical presentation as the patient is the only one capable of sitting and walking alone. Of the six mutations, two are de novo missense changes affecting highly conserved aminoacid residues, c.215 T>C p.Ile72Thr and c.380A>G p.His127Arg (present in a mosaic condition) found in two girls with the most severe clinical presentation, while the remaining are the splicing c.145+2 T>C and c.2376+5G>A, the c.1648C>T p.Arg550X and the MPLA-identified c.162-99del261 mutation. RNA characterisation of four mutations revealed the aberrant transcript of the missense allele (case 2) and not the stop mutation (case 3), but also allowed the splicing mutation (case 1) and the c.-162-99del261 (case 4) to be categorised as truncating. The obtained data reinforce the view that a more severe phenotype is due more to an altered protein than haploinsufficiency. Furthermore, the mutational repertoire of the CDKL5 gene is shown to be expanded by testing patients with phenotypical overlap to Rett syndrome and applying multiplex ligation-dependent probe amplification.
KW - Genotype-phenotype correlation
KW - Mutation screening
KW - RNA analysis
UR - http://www.scopus.com/inward/record.url?scp=70249084575&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70249084575&partnerID=8YFLogxK
U2 - 10.1007/s10048-009-0177-1
DO - 10.1007/s10048-009-0177-1
M3 - Article
C2 - 19241098
AN - SCOPUS:70249084575
VL - 10
SP - 241
EP - 250
JO - Neurogenetics
JF - Neurogenetics
SN - 1364-6745
IS - 3
ER -