PADDAS syndrome associated with hair dysplasia caused by a de novo missense variant of <i>PUM1</i>

Bonnemason‐Carrere, Paul; Morice‐Picard, Fanny; Pennamen, Perrine; Arveiler, Benoı̂t; Fergelot, Patricia; Goizet, Cyril; Hellegouarch, Mélanie; Lacombe, Didier; Plaisant, Claudio; Raclet, Virginie; Rooryck, Caroline; Lasseaux, Eulalie

doi:10.1002/ajmg.a.61127

Cited by 6 publications

(5 citation statements)

References 12 publications

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“…Since our initial study describing PUM1-related diseases (10), we and others have identified additional PADDAS and PRCA patients (10,(54)(55)(56). In our cohort, the R1147W mutation accounts for the majority of PADDAS patients, and T1035S for the majority of PRCA, which supports the value of studying these particular two mutations.…”

Section: Discussionsupporting

confidence: 75%

“…Since our initial study describing PUM1-related diseases (Gennarino et al, 2018), we and others have identified additional PADDAS and PRCA patients (Bonnemason-Carrere et al, 2019;Gennarino et al, 2018;Imaizumi et al, 2019;Lai et al, 2019). In our sample, R1147W accounts for the majority of PADDAS patients, and T1035S for the majority of PRCA, which supports the value of studying these particular two mutations as causing the most severe and the most mild forms of PUM1-related disease.…”

Section: Discussionsupporting

confidence: 70%

“…Since our initial study describing PUM1-related phenotypes (Gennarino et al, 2018), we and others have identified additional SCA47 patients (Bonnemason-Carrere et al, 2019;Gennarino et al, 2018;Imaizumi et al, 2019;Lai et al, 2019). In our cohort, heterozygous deletion and the R1147W mutation account for the majority of infantile-onset patients, and T1035S for the majority of adult-onset cases.…”

Section: Discussionmentioning

confidence: 88%

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Dosage sensitivity in Pumilio1-related phenotypes reflects distinct disease mechanisms

Botta

Chemiakine

et al. 2021

Preprint

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The RNA-binding protein (RBP) Pumilio1 (PUM1) is associated with two distinct diseases: a late-onset ataxia and a neurodevelopmental syndrome. The ataxia patients retain 75% of normal PUM1 levels, the syndromic patients ~50%, but this seems inadequate to explain the difference in phenotypes. We hypothesized that mild disease results from dysregulation of PUM1 targets, whereas severe disease involves disruption of PUM1 complexes and deregulation of shared targets. We therefore developed a PUM1 interactome for the murine brain and found that PUM1 shares targets with several RBP interactors (PUM2, FMRP, AGO2, and RBFOX3). PUM1 haploinsufficiency destabilizes these RBPs to varying degrees by brain region and sex, and alters expression of their shared targets, but the milder disease-causing mutation affects only PUM1-specific targets. These data indicate that dosage-sensitive proteins can produce different phenotypes by different mechanisms, and that there may be more intimate cooperation among RBPs than expected.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 88%

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Dosage sensitivity in Pumilio1-related phenotypes reflects distinct disease mechanisms

Botta

Chemiakine

et al. 2021

Preprint

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“…Their findings revealed that the exon 22 of the PUM1 gene had a de novo heterozygous missense variant [NM_001020658: c.3439C > T (p.Arg1147Trp)], which is otherwise absent in population databases (dbSNP, ExAC, and GnomAD). Thus far, at least three unrelated patients with this variant have been reported ( 5 , 7 , 8 ), and all of them were de novo . Upon Western blotting analysis, it was found that the PUM1 protein stability was markedly compromised by this variant ( 5 ).…”

Section: Resultsmentioning

confidence: 99%

A de novo PUM1 Variant in a Girl With a Dravet-Like Syndrome: Case Report and Literature Review

Mai

et al. 2022

Front. Pediatr.

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In the recent 3 years, subjects with Pumilio1-associated developmental disability, ataxia, and seizure syndrome have been identified as harboring Pumilio homolog 1 (PUM1) mutations. However, the characteristics of the seizure phenotype remain to be elucidated. We herein described a 3-year-old female proband who was diagnosed with developmental and epileptic encephalopathy presenting with some features suggestive of a Dravet-like syndrome. For genetic analyses, trio-based whole-exome sequencing and array comparative genomic hybridization were performed. Consequently, a de novo heterozygous missense variant was identified in exon 22 of the PUM1 gene: NM_001020658: c.3439C > T (p.Arg1147Trp). Upon thoroughly reviewing the existing literature, nine cases of PUM1 mutation-related epilepsy were identified, and their clinical features were summarized. A relationship between PUM1 mutation and clinical manifestations characteristic of a Dravet-like syndrome was proposed. To our knowledge, this is the first report of a patient with PUM1 mutation presenting with a Dravet-like syndrome.

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“…PUM1 has been very recently reported as responsible for a new form of a developmental disorder named PADDAS syndrome. A recent study describes a patient with early-onset developmental delay, epilepsy, microcephaly, and hair dysplasia, with a de novo heterozygous missense variant of PUM1: c.3439C > T, p.(Arg1147Trp) [ 49 ].…”

Section: Main Factors Influencing Cognition In Epileptic Children And...mentioning

confidence: 99%

Epilepsy and Cognitive Impairment in Childhood and Adolescence: A Mini-Review

Felicia

Pastorino

Viggiano

et al. 2023

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Managing epilepsy in people with intellectual disability remains a therapeutic challenge and must take into account additional issues such as diagnostic difficulties and frequent drug resistance. Advances in genomic technologies improved our understanding of epilepsy and raised the possibility to develop patients-tailored treatments acting on the key molecular mechanisms involved in the development of the disease. In addition to conventional antiseizure medications (ASMs), ketogenic diet, hormone therapy and epilepsy surgery play an important role especially in cases of drug resistance. This review aims to provide a comprehensive overview of the mainfactors influencing cognition in children and adolescents with epilepsy and the main therapeutic options available for the epilepsies associated with intellectual disability.

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PADDAS syndrome associated with hair dysplasia caused by a de novo missense variant of PUM1

Cited by 6 publications

References 12 publications

Dosage sensitivity in Pumilio1-related phenotypes reflects distinct disease mechanisms

Dosage sensitivity in Pumilio1-related phenotypes reflects distinct disease mechanisms

A de novo PUM1 Variant in a Girl With a Dravet-Like Syndrome: Case Report and Literature Review

Epilepsy and Cognitive Impairment in Childhood and Adolescence: A Mini-Review

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