A fascination with chromosome rescue in uniparental disomy: Mendelian recessive outlaws and imprinting copyrights infringements

Engel, Eric

doi:10.1038/sj.ejhg.5201619

Cited by 118 publications

(115 citation statements)

References 78 publications

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“…In myeloma, CN-LOH was suspected to be a new oncogenic mechanism using the genome-wide analysis, as the frequency of CN-LOH and CNA was higher in active MM than in the smoldering entity [22]. The frequency or the length of CN-LOH might also be an indirect measure of genomic instability in WM [23], and interestingly we have only observed large CN-LOHs in patients with symptomatic WM disease, in combination to higher frequency of genomic alterations.…”

Section: Discussionmentioning

confidence: 99%

Genome wide SNP array identified multiple mechanisms of genetic changes in Waldenstrom macroglobulinemia

et al. 2013

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SNP array (SNPa) was developed to detect copy number alteration (CNA) and loss of heterozygosity (LOH) without copy number changes, CN-LOH. We aimed to identify novel genomic aberrations using SNPa in 31 WM with paired samples. Methylation status and mutation were analyzed on target genes. A total of 61 genetic aberrations were observed, 58 CNA (33 gains, 25 losses) in 58% of patients and CN-LOH in 6% of patients. The CNA were widely distributed throughout the genome, including 12 recurrent regions and identified new cryptic clonal chromosomal lesions that were mapped. Gene set expression analysis demonstrated a relationship between either deletion 6q or gain of chromosome 4 and alteration of gene expression profiling. We then studied methylation status and sought for mutations in altered regions on target genes. We observed methylation of DLEU7 on chromosome 13 in all patients (n 5 12) with WM, and mutations of CD79B/CD79A genes (17q region), a key component of the BCR pathway, in 15% of cases. Most importantly, higher frequency of 3 CNA was observed in symptomatic WM. In conclusion, this study expands the view of the genomic complexity of WM, especially in symptomatic WM, including a potentially new mechanism of gene dysfunction, acquired uniparental disomy/CN-LOH. Finally, we have identified new potential target genes in WM, such as DLEU7 and CD79A/B. Am. J.

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Section: Discussionmentioning

confidence: 99%

Genome wide SNP array identified multiple mechanisms of genetic changes in Waldenstrom macroglobulinemia

et al. 2013

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“…The existence of large regions of germline homozygosity are rare and are more commonly associated with particular recessive disorders. 28 …”

Section: Pattern Of Abnormalities In Paired Fl and T-fl Biopsiesmentioning

confidence: 99%

Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma

et al. 2007

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Single-nucleotide polymorphism (SNP) array analysis was performed using the 10K GeneChip array on a series of 26 paired follicular lymphoma (FL) and transformed-FL (t-FL) biopsies and the lymphoma cell lines SCI-1, DoHH2 and RL2261. Regions of acquired homozygosity were detected in 43/52 (83%) primary specimens with a mean of 1.7 and 3.0 aberrations in the FL and t-FL, respectively. A notable feature was the occurrence of recurring sites of acquired uniparental disomy (aUDP) on 6p, 9p, 12q and 17p in cell lines and primary samples. Homozygosity of 9p and 17p arose predominantly in t-FL and in three cases rendered the cell homozygous for a preexisting mutation of either CDKN2A or TP53. These data suggest that mutation precedes mitotic recombination, which leads to the removal of the remaining wild-type allele. In all, 18 cases exhibited abnormalities in both FL and t-FL samples. In 10 cases blocks of homozygosity were detected in FL that were absent in the subsequent t-FL sample. These differences support the notion that FL and t-FL may arise in a proportion of patients by divergence from a common malignant ancestor cell rather than by clonal evolution from an antecedent FL.

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“…In this paper, we describe one of the 'Mendelian outlaws' as entitled by Engel. 46 In uniparental disomy, the proband has a normal copy number of chromosomes, but for one chromosome pair both chromosomes have been inherited from one parent. In uniparental isodisomy, it is two copies of the same chromosome that are inherited.…”

Section: Discussionmentioning

confidence: 99%

“…Uniparental isodisomy may occur by trisomy rescue, gamete complementation or monosomy rescue ( Figure 6). 46 In trisomy rescue, a disomic gamete generated by non-disjunction of the chromosomes in the second meiotic division meets a normal gamete creating a trisomic zygote. The loss of the extra chromosome then either generates a normal zygote or a zygote with uniparental isodisomy.…”

Section: Discussionmentioning

confidence: 99%

Complement factor H deficiency and endocapillary glomerulonephritis due to paternal isodisomy and a novel factor H mutation

et al. 2011

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Complement factor H (CFH) is a regulator of the alternative complement activation pathway. Mutations in the CFH gene are associated with atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II and C3 glomerulonephritis. Here, we report a 6-month-old CFH-deficient child presenting with endocapillary glomerulonephritis rather than membranoproliferative glomerulonephritis (MPGN) or C3 glomerulonephritis. Sequence analyses showed homozygosity for a novel CFH missense mutation (Pro139Ser) associated with severely decreased CFH plasma concentration (o6%) but normal mRNA splicing and expression. The father was heterozygous carrier of the mutation, but the mother was a non-carrier. Thus, a large deletion in the maternal CFH locus or uniparental isodisomy was suspected. Polymorphic markers across chromosome 1 showed homozygosity for the paternal allele in all markers and a lack of the maternal allele in six informative markers. This combined with a comparative genomic hybridization assay demonstrated paternal isodisomy. Uniparental isodisomy increases the risk of homozygous variations in other genes on the affected chromosome. Therefore, we analyzed other susceptibility genes on chromosome 1 and found no sequence variation in membrane cofactor protein, but homozygosity for the common deletion of CFH-related proteins 1 and 3, which may contribute to the early onset of disease.

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A fascination with chromosome rescue in uniparental disomy: Mendelian recessive outlaws and imprinting copyrights infringements

Cited by 118 publications

References 78 publications

Genome wide SNP array identified multiple mechanisms of genetic changes in Waldenstrom macroglobulinemia

Genome wide SNP array identified multiple mechanisms of genetic changes in Waldenstrom macroglobulinemia

Genome-wide detection of recurring sites of uniparental disomy in follicular and transformed follicular lymphoma

Complement factor H deficiency and endocapillary glomerulonephritis due to paternal isodisomy and a novel factor H mutation

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