Clinical characterization of a<i>PUF60</i>variant in a patient with Dubowitz‐like syndrome

Alkhunaizi, Ebba; Braverman, Nancy

doi:10.1002/ajmg.a.60691

Cited by 9 publications

(19 citation statements)

References 24 publications

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“…reported in seven patients with VRJS, four of whom are female, a prevalence far above the population rate of 1 in 40 to 1 in 400 individuals and in which there is a known and significant male preponderance (Biavati et al, 2020;El Chehadeh et al, 2017;Isidor & David, 2015;Low et al, 2017) In combining our detailed phenotypic data with the previously reported, and variably phenotyped patients, we further refine the known frequencies of features associated with VRJS (Table 3). 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%) (Alkhunaizi & Braverman, 2019;Dauber et al, 2013;Deciphering Developmental Disorders, 2017;El Chehadeh et al, 2017;Fromer et al, 2014;Graziano et al, 2017;Haug et al, 2021;Isidor & David, 2015;Jourdain et al, 2020;Kernohan et al, 2018;Latypova et al, 2021;Low et al, 2017;Moccia et al, 2018;Santos-Simarro et al, 2017;Q. Xu et al, 2018;Yamada et al, 2020;Zanolli et al, 2020;Zhao et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…The mutational spectrum of PUF60 includes frameshift, splice‐site, and missense variants. Pathogenic missense variants published to date are located within exons that encode the RRM1 and the UHM binding domains, suggesting that their alteration affects protein function and causes disease (Alkhunaizi & Braverman, 2019; Dauber et al, 2013; El Chehadeh et al, 2017; Graziano et al, 2017; Kernohan et al, 2018; Low et al, 2017; Moccia et al, 2018). PUF60 is homologous to another splicing factor, U2AF65 and RNAseq studies have shown that PUF60 and U2AF65 have opposing effects on exon splicing of many genes with PUF60 appearing to act mainly as an activator of splicing (Kralovicova et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…To date, 30 substantively phenotyped patients (Table S1) with VRJS due to PUF60 SNVs have been reported in peer-reviewed publications (Alkhunaizi & Braverman, 2019;Charzewska et al, 2018;Dauber et al, 2013;El Chehadeh et al, 2017;Graziano et al, 2017;Isidor & David, 2015;Latypova et al, 2021;Low et al, 2017;Moccia et al, 2018;Santos-Simarro et al, 2017;Q. Xu et al, 2018;Yamada et al, 2020;Zhao et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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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: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…The minimal common deletion found encompassed 3 genes including SCRIB and PUF60 and displayed most of the cardinal features of VRJS 29 . Although PUF60 appears to be a major driver of VRJS syndrome 29,[57][58][59][60][61][62][63][64] , neurological features were reported in a much lower proportion, indicating that PUF60 CNVs may not be their sole cause. From the human genetics standpoint, any VRJS-related phenotype due to SCRIB loss may prove difficult to observe because most SCRIB mutations lead to NTDs so deleterious that they may obscure more "subtle" phenotypes [20][21][22][23] .…”

Section: Discussionmentioning

confidence: 97%

Early loss of Scribble affects cortical development and interhemispheric connectivity resulting in psychomotor dysregulation

Ezan¹,

Moreau²,

Mamo³

et al. 2019

Preprint

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226/300 words) 29 Neurodevelopmental disorders often arise from combined defects in processes 30 including cell proliferation, differentiation, neuronal migration, axonal pathfinding and 31 commissure formation. Cell polarity proteins serve as a nexus to transduce signals for 32 the establishment of these essential processes. Scribble (Scrib) is an evolutionarily 33 conserved polarity protein that is known to regulate the establishment of apicobasal and 34 planar cell polarity. Mutations in the human SCRIB gene are associated with neural tube 35 defects and this gene is located in the minimal critical region deleted in the rare 36 Verheij/8q24.3 deletion syndrome. In the present study, we evaluated the contribution of 37 Scrib to some of the neurological features found in patients with this syndrome, 38 including microcephaly and corpus callosum agenesis. Using various brain-specific 39 conditional mouse mutants and in utero electroporation experiments, we assessed the 40 impact of the spatio-temporal selective Scrib deletion on brain morphogenesis and 41 animal behavior. Our results showed that global embryonic deletion of Scrib in the 42 telencephalon lead to a reduction of cortical thickness and an alteration of 43 interhemispheric connectivity. In addition, we identified cell-autonomous effects of Scrib 44 on neuronal migration, and we suggest a non-cell-autonomous effect in axonal 45 guidance. Finally, comparative behavioral analysis showed that mice with Scrib 46 invalidation have psychomotor deficits. Altogether, our mouse models recapitulate a 47 number of the phenotypes associated with Verheij/8q24.3 deletion syndrome patients, 48 supporting the possibility that Scrib contributes to this rare disease. 49 50 callosum 53 3 55Author Summary (176/200 words) 56 The mammalian brain, seat of cognitive and behavioral processing, is the result of 57 numerous, complex but coordinated mechanisms of development such as cell 58 proliferation, migration, neuritogenesis, synaptogenesis and neural network formation. 59Patients with disruptions in these fundamental processes will typically exhibit 60 neurodevelopmental disorders. As such, the rare Verheij syndrome is a condition where 61 patients display some neurological features such as microcephaly (dramatic reduction in 62 brain cortical size) or agenesis of the corpus callosum (loss of the main commissure 63 between hemispheres). The human gene SCRIB is included within a region, identified 64 as 8q24.3, which is deleted in patients with this syndrome. In this paper, we generated 65 mouse models to assess the consequences of selective genetic inactivation of Scrib on 66 the brain architecture and function. From the neuroanatomical standpoint, we show that 67 Scrib controls the formation of the cerebral cortex and the corpus callosum. This is 68 correlated with behavioral deficits such as disrupted locomotion, learning and memory. 69Altogether, this work validates the association between Scrib loss and the brain-70 associated clinical features obs...

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“…Among 32 patients who were reported to have deletions or de novo pathogenic variants of PUF60 (MIM#604819), the degree of clinical severity was relatively diverse, and no apparent genotype–phenotype correlations have been described so far (Alkhunaizi & Braverman, 2019; Dauber et al, 2013; El Chehadeh et al, 2016; Graziano et al, 2017; Low et al, 2017; Moccia et al, 2018; Santos‐Simarro et al, 2017; Verheij et al, 2009; Xu et al, 2018; Zhao et al, 2018). The PUF60 protein has two central RNA recognition motifs, RRM1 and RRM2, and a C′ terminal UHM (U2AF‐homology motif) motif (Corsini et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Protein elongation variant of PUF60: Milder phenotypic end of the Verheij syndrome

Yamada

Uehara

Suzuki

et al. 2020

American J of Med Genetics Pt A

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The PUF60 gene encodes a ubiquitously expressed essential splicing factor that is recruited to the U2snRNA complex. The complex binds to the 3 0 splice site of exons in specific target genes and regulates the inclusion or exclusion of such exons. Recently, pathogenic variants of PUF60 have been shown to cause a relatively specific and potentially recognizable pattern of malformation referred to as Verheij syndrome. Here, we report a 12-year-old female patient with a de novo mutation in PUF60 whose phenotype was representative of the milder end of the phenotypic spectrum of Verheij syndrome; the de novo mutation was a frameshift mutation p. (Ser558Cysfs*21) that resulted in the addition of 21 extra amino acids at the carboxy end of the protein. Among the frequent features of Verheij syndrome, the patient exhibited coloboma, cervical spinal segmentation defects, and borderline intellectual functioning, but lacked cardiac abnormalities, deafness, and urogenital abnormalities. The results of RNA analysis using peripheral blood showed the escape of the mutant allele from nonsense-mediated mRNA decay, possibly accounting for the mild phenotype in the presently reported patient. Based on our clinical observations, we inferred that two embryologic processes, closure of the ocular plate and cervical spinal segmentation, are particularly susceptible to deficient PUF60-mediated splicing regulation, compared with other embryogenetic processes leading to the central nervous system, heart, ear, and kidney.

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Clinical characterization of aPUF60variant in a patient with Dubowitz‐like syndrome

Cited by 9 publications

References 24 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

Early loss of Scribble affects cortical development and interhemispheric connectivity resulting in psychomotor dysregulation

Protein elongation variant of PUF60: Milder phenotypic end of the Verheij syndrome

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