Guenther, Sven, Elert-Dobkowska, Ewelina, Soehn, Anne S., Hinreiner, Sophie, Yoon, Grace, Heller, Raoul, Hellenbroich, Yorck, Huebner, Christian A., Ray, Peter N., Hehr, Ute, Bauer, Peter, Sulek, Anna ORCID: 0000-0003-2975-4888 and Beetz, Christian ORCID: 0000-0001-7061-2895 (2016). High Frequency of Pathogenic Rearrangements in SPG11 and Extensive Contribution of Mutational Hotspots and Founder Alleles. Hum. Mutat., 37 (7). S. 703 - 710. HOBOKEN: WILEY. ISSN 1098-1004

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Abstract

Biallelic loss-of-function mutations in SPG 11 cause a wide spectrum of recessively inherited, neuro-degenerative disorders including hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis, and Charcot-Marie-Tooth disease. By comprehensive screening of three large cohorts of HSP index patients, we identified 83 alleles with small mutations and 13 alleles that carry large genomic rearrangements. Including relevant data from previous studies, we estimate that copy number variants (CNVs) account for similar to 19% of pathogenic SPG11 alleles. The breakpoints for all novel and some previously reported CNVs were determined by long-range PCR and sequencing. This revealed several Alu-associated recombination hotspots. We also found evidence for additional mutational mechanisms, including for a two-step event in which an Alu retrotransposition preceded the actual rearrangement. Apparently independent samples with identical breakpoints were analyzed by microsatellite PCRs. The resulting haplotypes suggested the existence of two rearrangement founder alleles. Our findings widen the spectra of mutations and mutational mechanisms in SPG11, underscore the pivotal role played by Alus, and are of high diagnostic relevance for a wide spectrum of clinical phenotypes including the most frequent form of recessive HSP. (C) 2016 Wiley Periodicals, Inc.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Guenther, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Elert-Dobkowska, EwelinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soehn, Anne S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hinreiner, SophieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yoon, GraceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heller, RaoulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hellenbroich, YorckUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huebner, Christian A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ray, Peter N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hehr, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bauer, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sulek, AnnaUNSPECIFIEDorcid.org/0000-0003-2975-4888UNSPECIFIED
Beetz, ChristianUNSPECIFIEDorcid.org/0000-0001-7061-2895UNSPECIFIED
URN: urn:nbn:de:hbz:38-271489
DOI: 10.1002/humu.23000
Journal or Publication Title: Hum. Mutat.
Volume: 37
Number: 7
Page Range: S. 703 - 710
Date: 2016
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1098-1004
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
HEREDITARY SPASTIC PARAPLEGIA; COPY-NUMBER MUTATIONS; GENE REARRANGEMENTS; DELETION; SPATACSIN; RECOMBINATION; SPECTRUM; RESOLUTION; PHENOTYPE; DATABASEMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/27148

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