A 20.7 kb Deletion within the Factor VIII Gene Associated with LINE-1 Element Insertion

Water, Neil Van de; Williams, Ruth; Ockelford, Paul; Browett, Peter

doi:10.1055/s-0037-1615098

Cited by 39 publications

(2 citation statements)

References 25 publications

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“…L1s cannot only propagate their own sequences but also mobilize other RNA such as that of Alu transposons [Boeke, ; Dewannieux et al., ], SVA [Ostertag et al., ; Hancks et al., ; Raiz et al., ], and other cellular transcripts [Esnault et al., ; Zhang et al., ; Hancks and Kazazian, ]. Recent research has documented that L1 activity has directly contributed to evolution of gene structure and rewiring of gene regulatory sequences [Van de Water et al., ; Goodier et al., ; Pickeral et al., ; Zemojtel et al., ; Zemojtel et al., ; Kunarso et al., ; Schmidt et al., ; Ward et al., ]. Insertion of L1s in gene loci can interfere with gene expression and lead to aberrant splicing [Kingsmore et al., ; Mulhardt et al., ], frameshift, or a change in domain of expression [Wheelan et al., ; Zemojtel et al., ].…”

Section: Introductionmentioning

confidence: 99%

Recessive Inheritance of Population-Specific Intronic LINE-1 Insertion Causes a Rotor Syndrome Phenotype

et al. 2015

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Sequences of long-interspersed elements (LINE-1, L1) make up ∼17% of the human genome. De novo insertions of retrotransposition-active L1s can result in genetic diseases. It has been recently shown that the homozygous inactivation of two adjacent genes SLCO1B1 and SLCO1B3 encoding organic anion transporting polypeptides OATP1B1 and OATP1B3 causes a benign recessive disease presenting with conjugated hyperbilirubinemia, Rotor syndrome. Here, we examined SLCO1B1 and SLCO1B3 genes in six Japanese diagnosed with Rotor syndrome on the basis of laboratory data and laparoscopy. All six Japanese patients were homozygous for the c.1738C>T nonsense mutation in SLCO1B1 and homozygous for the insertion of a ∼6.1-kbp L1 retrotransposon in intron 5 of SLCO1B3, which altogether make up a Japanese-specific haplotype. RNA analysis revealed that the L1 insertion induced deleterious splicing resulting in SLCO1B3 transcripts lacking exon 5 or exons 5-7 and containing premature stop codons. The expression of OATP1B1 and OATP1B3 proteins was not detected in liver tissues. This is the first documented case of a population-specific polymorphic intronic L1 transposon insertion contributing to molecular etiology of recessive genetic disease. Since L1 activity in human genomes is currently seen as a major source of individual genetic variation, further investigations are warranted to determine whether this phenomenon results in other autosomal-recessive diseases.

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Section: Introductionmentioning

confidence: 99%

Recessive Inheritance of Population-Specific Intronic LINE-1 Insertion Causes a Rotor Syndrome Phenotype

et al. 2015

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“…To the best of our knowledge, only three cases of hemophilia A caused by LINE 1 insertion have been published to date. These consisted of such insertions at exon 14 in two patients, together with a large deletion spanning exons 15–20 of one patient . To date, there is no information regarding the association of FVIII inhibitors with the diagnosis of this extremely rare null mutation.…”

Section: Discussionmentioning

confidence: 99%

Spinal Epidural Hematoma Following Cupping Glass Treatment in an Infant With Hemophilia A

Fruchtman

Dardik

Barg

et al. 2016

Pediatric Blood & Cancer

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A deletion distinct from the classical homologous recombination of juvenile nephronophthisis type 1 (NPH1) allows exact molecular definition of deletion breakpoints

Betz¹,

Rensing²,

Schätzle³

et al. 2000

Hum. Mutat.

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Juvenile nephronophthisis, an autosomal recessive cystic kidney disease, is the most common genetic cause of end‐stage renal disease in children and young adults. We recently identified by positional cloning the causative gene, NPHP1. Its gene product nephrocystin may play a role in focal adhesion and adherens junction signaling. Approximately 80% of all patients with NPH1 carry large homozygous deletions, which contain the NPHP1 gene. These common deletions are positioned within a complex arrangement of large inverted and direct repeats, suggesting unequal recombination as a potential cause for their origin. In this study we have characterized the deletion breakpoints in a family with juvenile nephronophthisis that bears a unique maternal deletion of the NPHP1 gene, which is not the result of an event of homologous recombination. We molecularly characterized the centromeric and telomeric deletion breakpoints by extensive genomic sequencing, Southern blot analysis, and cloning and sequencing of the junction fragment. We were able to exactly localize the breakpoints at the position of two guanines. The centromeric breakpoint was positioned within intron 2 of the NPHP1 gene 360 bp downstream of the 5′ end of a complete LINE‐1 element. Multiple topoisomerase I and II consensus sequences were found at the breakpoint sites, suggesting the involvement of topoisomerase II in the deletion mechanism. These findings provide the first data on a potential mechanism for a deletion of the NPHP1 gene, that most likely is not the result of an event of homologous recombination and thereby distinct from the known common deletions. Hum Mutat 16:211–223, 2000. © 2000 Wiley‐Liss, Inc.

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A 20.7 kb Deletion within the Factor VIII Gene Associated with LINE-1 Element Insertion

Cited by 39 publications

References 25 publications

Recessive Inheritance of Population-Specific Intronic LINE-1 Insertion Causes a Rotor Syndrome Phenotype

Recessive Inheritance of Population-Specific Intronic LINE-1 Insertion Causes a Rotor Syndrome Phenotype

Spinal Epidural Hematoma Following Cupping Glass Treatment in an Infant With Hemophilia A

A deletion distinct from the classical homologous recombination of juvenile nephronophthisis type 1 (NPH1) allows exact molecular definition of deletion breakpoints

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