Mutation screen of the SIM1 gene in pediatric patients with early-onset obesity

Zegers, Doreen; Beckers, Sigri; Hendrickx, Rik; Camp, Jasmijn K. Van; Craemer, V de; Verrijken, An; Hoorenbeeck, Kim Van; Verhulst, Stijn; Rooman, Raoul; Desager, K N; Massa, Guy; Gaal, Luc F. Van; Hul, Wim Van

doi:10.1038/ijo.2013.188

Cited by 28 publications

(28 citation statements)

References 31 publications

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“…Loss-of-function variants in SIM1 may cause human obesity with or without PWS-like features. [37][38][39][40] However, in our study, SIM1 deletions in patients no. 5, 11, 12, and 13 were not associated with obesity.…”

Section: Cytogenetic and Molecular Resultscontrasting

confidence: 57%

“…51 Some patients with SIM1 loss-of-function variants have cognitive impairments and/or behavioural disorders. [38][39][40] However, none of those described to date had a history of neonatal hypotonia or feeding difficulties early in life. 38 Recently, a statistically significant association was demonstrated between the SIM1 SNP rs3734354 (Pro352Thr) and language impairment.…”

Section: Cytogenetic and Molecular Resultsmentioning

confidence: 99%

“…13,17 The first study identified a 4.1-Mb minimal critical region for PWS-like within the 6q16 cytogenetic band. 13 Recently, obesity and PWS-like syndrome have been ascribed to loss-of-function variants in the single-minded 1 (SIM1) gene encompassed in 6q16 critical minimal region, [37][38][39][40] whereas a role for GRIK2 deletion in behavioural problems has been suggested. 13 Here, we describe 15 new patients (including one fetus) with 6q16 deletions, including 6q16.2 and/or 6q16.3 sub-bands, investigated by chromosomal microarray analysis.…”

Section: Introductionmentioning

confidence: 99%

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Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

et al. 2014

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4,5,6 6q16 deletions have been described in patients with a Prader-Willi-like (PWS-like) phenotype. Recent studies have shown that certain rare single-minded 1 (SIM1) loss-of-function variants were associated with a high intra-familial risk for obesity with or without features of PWS-like syndrome. Although SIM1 seems to have a key role in the phenotype of patients carrying 6q16 deletions, some data support a contribution of other genes, such as GRIK2, to explain associated behavioural problems. We describe 15 new patients in whom de novo 6q16 deletions were characterised by comparative genomic hybridisation or single-nucleotide polymorphism (SNP) array analysis, including the first patient with fetopathological data. This fetus showed dysmorphic facial features, cerebellar and cerebral migration defects with neuronal heterotopias, and fusion of brain nuclei. The size of the deletion in the 14 living patients ranged from 1.73 to 7.84 Mb, and the fetus had the largest deletion (14 Mb). Genotype-phenotype correlations confirmed the major role for SIM1 haploinsufficiency in obesity and the PWS-like phenotype. Nevertheless, only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency. This study in the largest series reported to date confirms that the PWS-like phenotype is strongly linked to 6q16.2q16.3 deletions and varies considerably in its clinical expression. The possible involvement of other genes in the 6q16.2q16.3-deletion phenotype is discussed.

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Section: Cytogenetic and Molecular Resultscontrasting

confidence: 57%

Section: Cytogenetic and Molecular Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

et al. 2014

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“…Furthermore, common variations in SIM1 were shown to be significantly associated with the variation of body mass index (BMI) in Pima Indians (12), while the association was far less marked in Europeans (13). Recently, we and others have demonstrated that rare loss-of-function mutations in SIM1 cause severe obesity in European individuals (14)(15)(16). In particular, we described eight heterozygous SIM1 substitutions in four obese children presenting with PWLS and in seven morbidly obese adults (14).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, Ramachandrappa et al identified 13 heterozygous SIM1 substitutions in 28 unrelated severely obese patients, of which seven (p.S71R, p.R171H, p.L238G, p.P497R, p.S550L, p.D707H, and p.T712I) significantly reduced transcriptional activity of SIM1 and cosegregated with obesity in families with variable penetrance (15). Finally, Zeghers et al reported two loss-offunction mutations (p.T481K and p.A517V) in two obese patients, without any details on their cognitive status (16). Overall, these studies demonstrated the strong contribution to obesity of rare loss-offunction mutations in SIM1 (14-16), yet the role of these mutations in developmental delay remained unclear.…”

Section: Introductionmentioning

confidence: 99%

Identification of two novel loss-of-function SIM1 mutations in two overweight children with developmental delay

Montagne

Raimondo

Delobel

et al. 2014

Obesity

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Objective: Several deletions of chromosome 6q, including SIM1, were reported in obese patients with developmental delay. Furthermore, rare loss-of-function SIM1 mutations were shown to contribute to severe obesity, yet the role of these mutations in developmental delay remained unclear. Here, SIM1 in children with neurodevelopmental abnormalities was screened and the functional effect of the identified mutations was investigated. Methods: SIM1 was sequenced in 283 children presenting with developmental delay and at least overweight. The effect of the identified mutations on SIM1 transcriptional activity in stable human cell lines was assessed using luciferase gene reporter assays. Results: Two novel mutations (c.886A>G/p.R296G and c.925A>G/p.S309G) in two boys with variable degrees of cognitive deficits and weight issues were identified. The child mutated for p.R296G presented with a generally more severe phenotype than the p.S309G carrier (obesity, compulsive eating, neonatal hypotonia versus overweight only), while both mutations had strong loss-of-function effects on SIM1 transcriptional activity. Conclusions: Severe loss-of-function SIM1 mutations can be associated with a spectrum of developmental delay phenotypes and obesity. Our data suggest that SIM1 sequencing should be performed more systematically in patients with developmental delay, even in the absence of severe obesity. These results deserve further SIM1 screening studies.

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Aberrant DNA methylation of DLX4 and SIM1 is a predictive marker for disease progression of uterine cervical low‐grade squamous intraepithelial lesion

Sakane

Taniyama

Miyamoto

et al. 2015

Diagnostic Cytopathology

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Mutation screen of the SIM1 gene in pediatric patients with early-onset obesity

Cited by 28 publications

References 31 publications

Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

Identification of two novel loss-of-function SIM1 mutations in two overweight children with developmental delay

Aberrant DNA methylation of DLX4 and SIM1 is a predictive marker for disease progression of uterine cervical low‐grade squamous intraepithelial lesion

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