Expanding the clinical and molecular spectrum of the CWC27-related spliceosomopathy

Brea‐Fernández, Alejandro; Cabanas, Paloma; Dacruz-Álvarez, David; Caamaño, Pilar; Limeres, Jacobo; Loidi, Lourdes

doi:10.1038/s10038-019-0664-7

Cited by 12 publications

(17 citation statements)

References 9 publications

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“…We report novel features in several patients of ethnically diverse such as CWC27, RNU4ATAC, and SF3B4-related disorders, while a wide range of upper and lower limb anomalies are consistent features of almost all craniofacial spliceosomopathies (Beauchamp et al, 2020;Brea-Fernández et al, 2019). Additionally, Patient 1 has stenosis of the left pulmonary artery and left coronary stenosis; cardiac features not previously reported in association with PUF60 variants.…”

Section: Discussionmentioning

confidence: 54%

The diverse pleiotropic effects of spliceosomal protein PUF60: A case series of Verheij syndrome

Fennell

Baxter

Berkovic

et al. 2022

American J of Med Genetics Pt A

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Verheij syndrome (VRJS) is a rare craniofacial spliceosomopathy presenting with craniofacial dysmorphism, multiple congenital anomalies and variable neurodevelopmental delay. It is caused by single nucleotide variants (SNVs) in PUF60 or interstitial deletions of the 8q24.3 region. PUF60 encodes a splicing factor which forms part of the spliceosome. To date, 36 patients with a sole diagnosis of VRJS due to diseasecausing PUF60 SNVs have been reported in peer-reviewed publications. Although the depth of their phenotyping has varied greatly, they exhibit marked phenotypic heterogeneity. We report 10 additional unrelated patients, including the first described patients of Khmer, Indian, and Vietnamese ethnicities, and the eldest patient to date, with 10 heterozygous PUF60 variants identified through exome sequencing, 8 previously unreported. All patients underwent deep phenotyping identifying variable dysmorphism, growth delay, neurodevelopmental delay, and multiple congenital anomalies, including several unique features. The eldest patient is the only reported individual with a germline variant and neither neurodevelopmental delay nor intellectual disability. In combining these detailed phenotypic data with that of previously reported patients (n = 46), we further refine the known frequencies of features associated with VRJS. These include neurodevelopmental delay/intellectual disability (98%), axial skeletal anomalies (74%), appendicular skeletal anomalies (73%), oral anomalies (68%), short stature (66%), cardiac anomalies (63%), brain malformations (48%), hearing loss (46%), microcephaly (41%), colobomata (38%), and other ocular anomalies (65%). This case series, incorporating three patients from previously unreported ethnic backgrounds, further delineates the broad pleiotropy and mutational spectrum of PUF60 pathogenic variants.

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Section: Discussionmentioning

confidence: 54%

The diverse pleiotropic effects of spliceosomal protein PUF60: A case series of Verheij syndrome

Fennell

Baxter

Berkovic

et al. 2022

American J of Med Genetics Pt A

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“…In contrast, the C allele (C-C-C) should be potentially protective CWC27 is one kind of cyclophilin, which is involved in the binding of proline-containing peptides and participates in protein folding. CWC27 has an N-terminal PPIase domain containing a proline-binding pocket to bind to proline and a large C-terminal repetitive low complexity region of unknown function [29]. The disruptions of CWC27 can lead to a spectrum of isolation from syndromic phenotypes, including retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurological defects [30,31].…”

Section: Discussionmentioning

confidence: 99%

Susceptibility Loci in SLC15A1, UGT1A3, and CWC27 Genes Associated with Bladder Cancer in the Northeast Chinese Population

Guo

2022

BioMed Research International

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Bladder cancer (BCa) is an increasingly severe clinical and public health issue. Therefore, we aim to investigate BCa susceptibility loci in the Chinese population. In this study, 487 BCa patients and 563 controls were recruited from the First Affiliated Hospital of China Medical University from July 2015 to September 2020. A total of ten single-nucleotide polymorphisms (SNPs) in solute carrier family 15 member 1 (SLC15A1), CWC27 spliceosome associated cyclophilin (CWC27), or UDP glucuronosyltransferase family 1 member A3 (UGT1A3) genes were genotyped. The associations between the candidate SNPs and BCa were analyzed using genotype and haplotype analysis. The results demonstrated that Rs4646227 of SLC15A1 has a significant association with BCa. The patients with CG (OR =2.513, p < 0.05 ) and GG (OR =2.859, p < 0.05 ) genotypes had an increasing risk of BCa compared with the CC genotype. For the CWC27 gene, genotypic frequency analysis revealed that the GT or TT genotype of rs2042329 and the CT or TT genotype of rs1870437 were more frequent in BCa patients than those in the control group, indicating that these genotypes were associated with a higher risk of BCa (all p < 0.05 ). Haplotypes of SLC15A1, UGT1A3, and CWC27 genes found that the C-C-C haplotype of SLC15A1 was associated with a lower risk of BCa while the C-G-C haplotype was associated with a higher risk. For the UGT1A3 gene, a moderate protective effect was observed with the most frequent T-T-C haplotype, and for the CWC27 gene, most of the haplotypes showed no association with BCa, except the G-G-C-T haplotype (order of SNPs: rs2042329-rs7735338-rs1870437-rs2278351, OR =0.81, p =0.038). In sum, this study indicated that rs2042329 and rs1870437 in the CWC27 gene and rs4646227 in the SLC15A1 gene are independent indicators for BCa risk in Chinese people. Further large-scale studies are required to validate these findings. Also, this study provided the theoretical basis for developing new therapeutic drug targeting of BCa.

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“…However, mRNA for all three is expressed at medium to high levels in human germ cells and all are widely expressed during spermatogenesis 31 . Specifically, CDC5L is a component of the PRP19-CDC5L complex that forms an integral part of the spliceosome and is required for activating pre-mRNA splicing 32 , as is CWC27 33 . U2AF2 plays a role in pre-mRNA splicing and 3′-end processing 34 .…”

Section: Resultsmentioning

confidence: 99%

A de novo paradigm for male infertility

Oud¹,

Smits²,

Smith

et al. 2022

Nat Commun

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De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10−5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10−4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.

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Expanding the clinical and molecular spectrum of the CWC27-related spliceosomopathy

Cited by 12 publications

References 9 publications

The diverse pleiotropic effects of spliceosomal protein PUF60: A case series of Verheij syndrome

The diverse pleiotropic effects of spliceosomal protein PUF60: A case series of Verheij syndrome

Susceptibility Loci in SLC15A1, UGT1A3, and CWC27 Genes Associated with Bladder Cancer in the Northeast Chinese Population

A de novo paradigm for male infertility

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