Homozygous deletion of DIS3L2 exon 9 due to non-allelic homologous recombination between LINE-1s in a Japanese patient with Perlman syndrome

Higashimoto, Ken; Maeda, Toshiyuki; Okada, Jiro; Ohtsuka, Yasufumi; Sasaki, Kensaku; Hirose, Akiko; Nomiyama, Makoto; Takayanagi, Tetsuya; Fukuzawa, Ryuji; Yatsuki, Hitomi; Koide, Kayoko; Nishioka, Kusuki; Joh, Keiichiro; Watanabe, Yoriko; Yoshiura, Koh-ichiro; Soejima, Hidenobu

doi:10.1038/ejhg.2013.45

Cited by 17 publications

(21 citation statements)

References 17 publications

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“…Our data therefore provide a road map for the functional dissection of uridylation‐triggered RNA decay. Notably, germline mutations in DIS3L2 have been shown to cause Perlman syndrome in humans, a congenital overgrowth disorder with high neonatal mortality and predisposition to Wilms’ tumor (Astuti et al , ; Higashimoto et al , ). But the disease‐causing molecular targets of Dis3l2 remain enigmatic.…”

Section: Discussionmentioning

confidence: 99%

Molecular basis for cytoplasmic RNA surveillance by uridylation‐triggered decay in Drosophila

et al. 2016

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The posttranscriptional addition of nucleotides to the 3 0 end of RNA regulates the maturation, function, and stability of RNA species in all domains of life. Here, we show that in flies, 3 0 terminal RNA uridylation triggers the processive, 3 0 -to-5 0 exoribonucleolytic decay via the RNase II/R enzyme CG16940, a homolog of the human Perlman syndrome exoribonuclease Dis3l2. Together with the TUTase Tailor, dmDis3l2 forms the cytoplasmic, terminal RNA uridylation-mediated processing (TRUMP) complex that functionally cooperates in the degradation of structured RNA. RNA immunoprecipitation and high-throughput sequencing reveals a variety of TRUMP complex substrates, including abundant noncoding RNA, such as 5S rRNA, tRNA, snRNA, snoRNA, and the essential RNase MRP. Based on genetic and biochemical evidence, we propose a key function of the TRUMP complex in the cytoplasmic quality control of RNA polymerase III transcripts. Together with high-throughput biochemical characterization of dmDis3l2 and bacterial RNase R, our results imply a conserved molecular function of RNase II/R enzymes as "readers" of destabilizing posttranscriptional marks-uridylation in eukaryotes and adenylation in prokaryotes-that play important roles in RNA surveillance.

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Section: Discussionmentioning

confidence: 99%

Molecular basis for cytoplasmic RNA surveillance by uridylation‐triggered decay in Drosophila

et al. 2016

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“…DIS3L2 was recently identified as causative gene for Perlman syndrome, although no obvious genotype‐phenotype correlations have been noted. DIS3L2 mutations that have to date been identified in only ten patients with Perlman syndrome (including ours) are shown in Table (Astuti et al, ; Higashimoto et al, ; Morris et al, ). All seven patients with short‐term survival had homozygous deletions of exon 6 or 9, which leads to the loss of the RNB domain in both alleles.…”

Section: Discussionmentioning

confidence: 77%

“…In addition, mutations of the DIS3L2 have been identified in seven families with Perlman syndrome. Homozygous deletions of nine or six were found in five families and other mutations in two families (Astuti et al, ; Higashimoto et al, ; Morris, Astuti, & Maher, ). Chang recently reported Dis3l2 functions as being the effector nuclease responsible for degrading uridylated pre‐let‐7 miRNAs in the Lin28–let‐7 pathway in embryonic stem cells (Chang, Triboulet, Thornton, & Gregory, ).…”

Section: Introductionmentioning

confidence: 99%

Long term survival of a patient with Perlman syndrome due to novel compound heterozygous missense mutations in RNB domain of DIS3L2

Soma

Higashimoto

Imamura

et al. 2017

American J of Med Genetics Pt A

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Perlman syndrome is a rare overgrowth syndrome characterized by polyhydramnios, macrosomia, distinctive facial appearance, renal dysplasia, and a predisposition to Wilms' tumor. The syndrome is often associated with a high neonatal mortality rate and there are few reports of long-term survivors. We studied a 6-year-old Japanese female patient, who was diagnosed with Perlman syndrome, with novel compound heterozygous mutations in DIS3L2 (c.[367-2A > G];[1328T > A]), who has survived long term. Most reported DIS3L2 mutations have been the homozygous deletion of exon 6 or exon 9, and these mutations would certainly have caused the loss of both RNA binding and degradation activity. We have identified new compound heterozygous mutations in the DIS3L2 of this long-term survivor of Perlman syndrome. The reason our patient has survived long-term would be a missense mutation (c.1328 T > A, p.Met443Lys) having retained RNA binding in both the cold-shock domains and the S1 domain, and through partial RNA degradation. If partial exonuclease functions remain in at least one allele, long-term survival may be possible. Further studies of Perlman syndrome patients with proven DIS3L2 mutations are needed to clarify genotype-phenotype correlation.

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“…However, NAHR mediated by L1 and HERV elements had been thought to rarely cause human diseases (Burwinkel and Kilimann, ). Indeed, until 2014 only four human diseases had been reported to be caused by L1‐mediated NAHR (Burwinkel and Kilimann, ; Higashimoto et al, ; Segal et al, ; Temtamy et al, ). However, recent reports have identified a recombination between L1 pairs at breakpoints of 44 pathogenic CNVs, suggesting that L1s‐mediated NAHR is likely to occur far more frequently than previously thought and is a crucial mechanism of structural rearrangement that contributes to genomic disorders (Startek et al, ).…”

Section: Discussionmentioning

confidence: 99%

A 590 kb deletion caused by non‐allelic homologous recombination between two LINE‐1 elements in a patient with mesomelia‐synostosis syndrome

Kohmoto

Naruto

Watanabe

et al. 2017

American J of Med Genetics Pt A

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Mesomelia-synostoses syndrome (MSS) is a rare, autosomal-dominant, syndromal osteochondrodysplasia characterized by mesomelic limb shortening, acral synostoses, and multiple congenital malformations due to a non-recurrent deletion at 8q13 that always encompasses two coding-genes, SULF1 and SLCO5A1. To date, five unrelated patients have been reported worldwide, and MMS was previously proposed to not be a genomic disorder associated with deletions recurring from non-allelic homologous recombination (NAHR) in at least two analyzed cases. We conducted targeted gene panel sequencing and subsequent array-based copy number analysis in an 11-year-old undiagnosed Japanese female patient with multiple congenital anomalies that included mesomelic limb shortening and detected a novel 590 Kb deletion at 8q13 encompassing the same gene set as reported previously, resulting in the diagnosis of MSS. Breakpoint sequences of the deleted region in our case demonstrated the first LINE-1s (L1s)-mediated unequal NAHR event utilizing two distant L1 elements as homology substrates in this disease, which may represent a novel causative mechanism of the 8q13 deletion, expanding the range of mechanisms involved in the chromosomal rearrangements responsible for MSS.

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Homozygous deletion of DIS3L2 exon 9 due to non-allelic homologous recombination between LINE-1s in a Japanese patient with Perlman syndrome

Cited by 17 publications

References 17 publications

Molecular basis for cytoplasmic RNA surveillance by uridylation‐triggered decay in Drosophila

Molecular basis for cytoplasmic RNA surveillance by uridylation‐triggered decay in Drosophila

Long term survival of a patient with Perlman syndrome due to novel compound heterozygous missense mutations in RNB domain of DIS3L2

A 590 kb deletion caused by non‐allelic homologous recombination between two LINE‐1 elements in a patient with mesomelia‐synostosis syndrome

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