A New Overgrowth Syndrome is due to Mutations in<i>RNF125</i>

Tenorio, Jair; Mansilla, Alicia; Valencia, María; Martínez‐Glez, Víctor; Romanelli, Valeria; Arias, Pedro; Castrejón, Nerea; Poletta, Fernando A.; Guillén‐Navarro, Encarna; Gordo, Gema; Mansilla, Elena; García-Santiago, Fé Amalia; González‐Casado, Isabel; Vallespín, Elena; Palomares, María; Mori, María Ángeles; Santos‐Simarro, Fernando; García‐Miñaúr, Sixto; Fernández, Luís; Mena, Rocío; Benito‐Sanz, Sara; Pozo, Ángela del; Silla, J.C.; Ibáñez, Kristina; López‐Granados, Eduardo; Martín‐Trujillo, Alex; Montaner, David; Heath, Karen E.; Campos‐Barros, Ángel; Dopazo, Joaquín; Nevado, Julián; Monk, David; Ruiz‐Pérez, Víctor L.; Lapunzina, Pablo

doi:10.1002/humu.22689

Cited by 33 publications

(43 citation statements)

References 20 publications

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“…As mentioned earlier, RNF135 encodes an E3 ubiquitin ligase; other ubiquitin ligase genes have already been implicated in the development of intellectual disability and autism (Tenorio et al 2014; reviewed by Tastet et al 2015). …”

Section: Co-deleted Genes With the Potential To Influence The Clinicamentioning

confidence: 96%

Emerging genotype–phenotype relationships in patients with large NF1 deletions

2017

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The most frequent recurring mutations in neurofibromatosis type 1 (NF1) are large deletions encompassing the NF1 gene and its flanking regions (NF1 microdeletions). The majority of these deletions encompass 1.4-Mb and are associated with the loss of 14 protein-coding genes and four microRNA genes. Patients with germline type-1 NF1 microdeletions frequently exhibit dysmorphic facial features, overgrowth/tall-for-age stature, significant delay in cognitive development, large hands and feet, hyperflexibility of joints and muscular hypotonia. Such patients also display significantly more cardiovascular anomalies as compared with patients without large deletions and often exhibit increased numbers of subcutaneous, plexiform and spinal neurofibromas as compared with the general NF1 population. Further, an extremely high burden of internal neurofibromas, characterised by >3000 ml tumour volume, is encountered significantly, more frequently, in non-mosaic NF1 microdeletion patients than in NF1 patients lacking such deletions. NF1 microdeletion patients also have an increased risk of malignant peripheral nerve sheath tumours (MPNSTs); their lifetime MPNST risk is 16–26%, rather higher than that of NF1 patients with intragenic NF1 mutations (8–13%). NF1 microdeletion patients, therefore, represent a high-risk group for the development of MPNSTs, tumours which are very aggressive and difficult to treat. Co-deletion of the SUZ12 gene in addition to NF1 further increases the MPNST risk in NF1 microdeletion patients. Here, we summarise current knowledge about genotype–phenotype relationships in NF1 microdeletion patients and discuss the potential role of the genes located within the NF1 microdeletion interval whose haploinsufficiency may contribute to the more severe clinical phenotype.

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Section: Co-deleted Genes With the Potential To Influence The Clinicamentioning

confidence: 96%

Emerging genotype–phenotype relationships in patients with large NF1 deletions

2017

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“…Interestingly, individuals with haploinsufficiency of RNF135 or RNF125, which encode other RNF proteins, have been associated recently (via alteration of ubiquitin signaling pathways) by us and others with macrocephaly and overgrowth in patients with dysmorphic features and ID. 58,59 Thus, additional efforts will be necessary to definitively establish how PIAS4, PIAS-like or other RNF proteins, may be involved in regulation of human head size.…”

Section: Genomic Context Deletion Size and Genes Implicatedmentioning

confidence: 99%

PIAS4 is associated with macro/microcephaly in the novel interstitial 19p13.3 microdeletion/microduplication syndrome

et al. 2015

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Array comparative genomic hybridization (aCGH) is a powerful genetic tool that has enabled the identification of novel imbalances in individuals with intellectual disability (ID), autistic disorders and congenital malformations. Here we report a 'genotype first' approach using aCGH on 13 unrelated patients with 19p13.3 submicroscopic rearrangement (11 deletions and 2 duplications) and review cases in the literature and in public databases. Shared phenotypic features suggest that these patients represent an interstitial microdeletion/microduplication syndrome at 19p13.3. Common features consist of abnormal head circumference in most patients (macrocephaly with the deletions and microcephaly with the duplications), ID with developmental delay (DD), hypotonia, speech delay and common dysmorphic features. The phenotype is associated with at least a~0.113 Mb critical region harboring three strong candidate genes probably associated with DD, ID, speech delay and other dysmorphic features: MAP2K2, ZBTB7A and PIAS4, an E3 ubiquitin ligase involved in the ubiquitin signaling pathways, which we hypothesize for the first time to be associated with head size in humans.

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“…Especially, striking is their role in endocrine disorders, in which several ubiquitin E3 ligases were related to growth disorders such as Tenorio syndrome (MIM 616260) which is caused by autosomal dominant heterozygous loss of function (LOF) variants in RNF125 , an E3 ubiquitin ligase protein, which acts as a negative regulator of the RIG‐I and PI3K‐AKT pathways. Clinical features of this condition include overgrowth, autoimmune disorders resembling Sjögren syndrome, ID, macrocephaly, hypoglycemia and enlarged ventricles.…”

Section: Introductionmentioning

confidence: 99%

Further definition of the proximal 19p13.3 microdeletion/microduplication syndrome and implication of PIAS4 as the major contributor

et al. 2020

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The proximal 19p13.3 microdeletion/microduplication (prox19p13.3del/dup) syndrome is a recently described disorder with common clinical features including developmental delay, intellectual disability, speech delay, facial dysmorphic features with ear defects, anomalies of the hands and feet, umbilical hernia and hypotonia. While deletions are associated with macrocephaly, patients with duplications have microcephaly. The smallest region of overlap in multiple patients (113.5 kb) included three genes and one pseudogene, with a suggested major role of PIAS4 in determination of the phenotype and head size in these patients. Here, we refine the prox19p13.3del/dup with four additional patients: two with microdeletions, one with microduplication and one family with single‐nucleotide nonsense variant in PIAS4. The patient with the PIAS4 loss of function variant displayed a phenotype quite similar to deletion patients ‐including the macrocephaly and many other core features of the syndrome. Patient's SNV was inherited from her mother who is similarly affected. Thus, our data indicate that PIAS4 is a major contributor to the proximal 19p13.3del/dup syndrome phenotype. In summary, we report the first patient with a pathogenic variant in PIAS4‐ and three additional rearrangements at the proximal 19p13.3 locus. These observations add further evidence about the molecular basis of this microdeletion/microduplication syndrome.

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A New Overgrowth Syndrome is due to Mutations inRNF125

Cited by 33 publications

References 20 publications

Emerging genotype–phenotype relationships in patients with large NF1 deletions

Emerging genotype–phenotype relationships in patients with large NF1 deletions

PIAS4 is associated with macro/microcephaly in the novel interstitial 19p13.3 microdeletion/microduplication syndrome

Further definition of the proximal 19p13.3 microdeletion/microduplication syndrome and implication of PIAS4 as the major contributor

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