Khani, M;
Taheri, H;
Shamshiri, H;
Moazzeni, H;
Hardy, J;
Bras, JT;
InanlooRahatloo, K;
... Elahi, E; + view all
(2021)
Deep geno- and phenotyping in two consanguineous families with CMT2 reveals HADHA as an unusual disease-causing gene and an intronic variant in GDAP1 as an unusual mutation.
Journal of Neurology
, 268
pp. 640-650.
10.1007/s00415-020-10171-4.
Preview |
Text (Accepted Manuscript)
Hardy_Deep geno- and phenotyping in two consanguineous families with CMT2 revealsHADHAas an unusual disease-causing gene and an intronic variant inGDAP1as an unusual mutation_AAM.pdf - Accepted Version Download (329kB) | Preview |
![[thumbnail of Supplementary Material]](https://discovery.ucl.ac.uk/style/images/fileicons/other.png) |
Spreadsheet (Supplementary Material)
Copy of Table 1.xlsx - Accepted Version Download (12kB) |
|
Spreadsheet (Supplementary Material)
Copy of Table 2.xlsx - Accepted Version Download (12kB) |
|
Spreadsheet (Supplementary Material)
Copy of Table 3.xlsx - Accepted Version Download (11kB) |
|
Spreadsheet (Supplementary Material)
Copy of Table S1.xlsx - Accepted Version Download (11kB) |
|
Spreadsheet (Supplementary Material)
Copy of Table S2.xlsx - Accepted Version Download (10kB) |
Preview |
Image (Supplementary Material)
Figure 1-300 dpi.tif - Accepted Version Download (3MB) | Preview |
Preview |
Image (Supplementary Material)
Figure 2-300 dpi.tif - Accepted Version Download (1MB) | Preview |
Preview |
Image (Supplementary Material)
Figure 3-300 dpi.tif - Accepted Version Download (6MB) | Preview |
Preview |
Image (Supplementary Material)
Figure 4-300dpi.tif - Accepted Version Download (778kB) | Preview |
Abstract
BACKGROUND: Charcot–Marie–Tooth (CMT) disease is a prevalent and heterogeneous peripheral neuropathy. Most patients affected with the axonal form of CMT (CMT2) do not harbor mutations in the approximately 90 known CMT-associated genes. We aimed to identify causative genes in two CMT2 pedigrees. METHODS: Neurologic examination, laboratory tests and brain MRIs were performed. Genetic analysis included exome sequencing of four patients from the two pedigrees. The predicted effect of a deep intronic mutation on splicing was tested by regular and real-time PCR and sequencing. RESULTS: Clinical data were consistent with CMT2 diagnosis. Inheritance patterns were autosomal recessive. Exome data of CMT2-101 did not include mutations in known CMT-associated genes. Sequence data, segregation analysis, bioinformatics analysis, evolutionary conservation, and information in the literature strongly implicated HADHA as the causative gene. An intronic variation positioned 23 nucleotides away from following intron/exon border in GDAP1 was ultimately identified as cause of CMT in CMT2-102. It was shown to affect splicing. CONCLUSION: The finding of a HADHA mutation as a cause of CMT is of interest because its encoded protein is a subunit of the mitochondrial trifunctional protein (MTP) complex, a mitochondrial enzyme involved in long chain fatty acid oxidation. Long chain fatty acid oxidation is an important source of energy for skeletal muscles. The mutation found in CMT2-102 is only the second intronic mutation reported in GDAP1. The mutation in the CMT2-102 pedigree was outside the canonical splice site sequences, emphasizing the importance of careful examination of available intronic sequences in exome sequence data.
| Type: | Article |
|---|---|
| Title: | Deep geno- and phenotyping in two consanguineous families with CMT2 reveals HADHA as an unusual disease-causing gene and an intronic variant in GDAP1 as an unusual mutation |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1007/s00415-020-10171-4 |
| Publisher version: | https://doi.org/10.1007/s00415-020-10171-4 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions. |
| Keywords: | Charcot-Marie-Tooth disease, Axonal CMT, CMT2, HADHA, GDAP1, Intronic mutation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10113148 |
Loading...
Loading...Loading...| 1. |  United States | 23 |
| 2. |  China | 16 |
| 3. |  Russian Federation | 3 |
| 4. |  United Kingdom | 3 |
| 5. |  Iran, Islamic Republic of | 2 |
| 6. |  Turkey | 1 |
| 7. |  South Africa | 1 |
| 8. |  United Arab Emirates | 1 |
| 9. |  Egypt | 1 |
| 10. |  Japan | 1 |
Archive Staff Only
 |
View Item |
