Genetic study of a Huntington's disease phenocopy |
Genetic study of a Huntington's disease phenocopy- Fengqing Xiang, Zhiping Zhang
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder.
The gene responsible for HD on chromosome 4p was identified in 1993. One "HD family" was referred to us for linkage analysis
in the predictive testing program in 1991.
Seven of the family members are affected and diagnosed as HD because of clinical
similarities. However, no CAG repeat expansions in the HD gene were detected in the affected individuals and the region containing
the HD gene was completely excluded.
In order to map the disease segregating in the family, whole genome screening
was performed in this HD family. A positive lod score of 3.01 was obtained which is the highest lod score by simulate test.
Several candidate genes from the mapping region are being screened for mutations.
Xiang, Fengqing
Genetic studies of neurological disorders: Rett syndrome and HD-like familial prion
disease.
Fredagen den 19 oktober 2001, kl. 10.00. Föreläsningssalen, Centrum för Molekylär Medicin,
Karolinska Sjukhuset.
Abstract:
Rett syndrome (RTT) is a severe childhood neurodevelopmental disorder, which almost
exclusively affects females with a prevalence of 1 in 10 000-15 000, >99% of the cases are sporadic. It is commonly thought
of as an X-linked dominant disorder lethal to males. Concordance among monozygotic twins and disease transmission in a few
familial cases suggest genetic aetiology of the disease.
Based on the hypothesis by Thomas that a high male to female ratio of germline
mutations can explain the lack of affected males in RTT and other X-linked dominant diseases, genomic screening of the whole
X chromosome was performed in order to identify the grand-paternal alleles in one RTT family with three generations. The results
indicate that the RTT gene is likely to be located on the telomere of X. Further investigations using eight additional families
narrowed down the region to Xq28, which was further confirmed by two other groups. Xq28 was then intensively screened for
RTT gene until Amir et al. identified mutations in the MECP2 gene.
Mutations of the MECP2 gene in our RTT familial and sporadic cases,
classical and atypical RTT, were detected in 35%. Mutations included missense, nonsense, deletion or insertion. Due to the
low mutation frequency, suggesting that other genes may be involved in the pathogenesis of RTT, mutation screening of six
additional candidate genes on the X or autosomal chromosomes (UBE1, UBE21 GdX, SOX3, GABRA3 and CDR2) was performed.
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Genetic studies of neurological disorders: Rett syndrome and HD-like familial
prion disease continued
These genes were selected based on clinical, pathological, and genetic grounds.
No mutation was found in these genes by direct sequencing. Furthermore, gene expression profiles of MECP2, GdX,
GABRA3 and LICAM were investigated using in situ hybridization. No gross differences were observed in brain neurons
from Rett patients comparing to normal controls.
To determine if X-chromosome inactivation (XCI) plays an important role in the
pathogenesis of RTT, we analysed XCI pattern in five RTT families. The result showed that all mothers and six out of eight
affected girls exhibited a totally skewed pattern of XCI and the paternally inherited X chromosome was active in the patients
with a skewed pattern of XCI. Genotyping of the whole X chromosome indicate that a potential locus responsible for the skewed
XCI in these families could be located on the short arm of the X chromosome. Mutation screening of MECP2 gene revealed
a mutation in only one of the five families. These data led us to propose a model for familial RTT transmission in which two
phenomena would be involved: an X-linked locus abnormally escaping XCI and the presence of a skewed XCI in carrier women.
Huntington's disease (HD) is an autosomal dominant neurodegenerative
disorder. The HD gene on chromosome 4p, containing a CAG repeat, was identified in 1993. A family with three generations was
referred to us for HD predictive testing. Seven affected family members were diagnosed as HD because of clinical and neuropathological
similarities. No CAG repeat expansions were detected and the region containing the HD gene was completely excluded by linkage
analysis.
In order to map the disease trait in this HD-like family, whole genome screening
was per performed using highly polymorphic DNA microsatellite markers. A Lod score of 3.01 was obtained in this family for
the marker D20S482 on chromosome 20p, which was the highest Lod score predicted by a simulation test. Haplotype analysis indicated
that the gene responsible for this disease was located in a region of 2.7 cM between markers D20S193 and D20S895. Candidate
genes from the mapped region were screened for mutations. A 194 bp octapeptide repeat expansion in the N-terminus of the PrP
gene was identified in all affected members and not in healthy individuals.
This indicates that the HD-like neurodegenerative disorder is in fact a familial
prion disease and suggests that clinicians should consider screening for prion gene mutation in individuals with HD-like diseases
in which the HD CAG repeat expansions are absent.
Keywords: Huntington's disease (HD), MECP2 gene, mutation,
linkage analysis, prion disease, prion protein (PrP), Rett syndrome (RTT), X-chromosome inactivation (XCI).
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List of papers
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Chromosome mapping of Rett syndrome: a likely candidate region
on the telomere of Xq.
Xiang F, Zhang Z, Clarke A, Joseluiz P, Sakkubai N, Sarojini B, Delozier-Blanchet CD, Hansmann
I, Edstrom L, Anvret M
J Med Genet, 1998; 35(4): 297-300
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Mutation screening in Rett syndrome patients.
Xiang F, Buervenich S, Nicolao P, Bailey ME, Zhang Z, Anvret M
J Med Genet, 2000;
37(4): 250-5
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Segregation of a totally skewed pattern of X chromosome inactivation
in four familial cases of Rett syndrome without MECP2 mutation: implications for the disease.
Villard L, Levy N, Xiang F, Kpebe A, Labelle V, Chevillard C, Zhang Z, Schwartz CE, Tardieu
M, Chelly J, Anvret M, Fontes M
J Med Genet, 2001; 38(7): 435-42
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A Huntington disease-like neurodegenerative disorder maps to chromosome
20p.
Xiang F, Almqvist EW, Huq M, Lundin A, Hayden MR, Edstrom L, Anvret M, Zhang Z
Am J Hum
Genet, 1998; 63(5): 1431-8
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Huntingtons disease phenocopy is a familial
disease.
Moore R, Xiang F, Monaghan J, Han D, Zhang Z, Edstrom L, Anvret M, Prusiner S
Am J Hum Genet, Submitted
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