Copy number variation (CNV) analysis and mutation analysis of the 6q14.1–6q16.3 genes SIM1 and MRAP2 in Prader Willi like patients

Geets, Ellen; Zegers, Doreen; Beckers, Sigri; Verrijken, An; Massa, Guy; Hoorenbeeck, Kim Van; Verhulst, Stijn; Gaal, Luc Van; Hul, Wim Van

doi:10.1016/j.ymgme.2016.01.003

Cited by 25 publications

(21 citation statements)

References 38 publications

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“…Hence, additional functional analyses could well reveal a functional effect of all nonsynonymous MRAP2 mutations. Taking this assumption forward, we detected association of nonsynonymous MRAP2 mutations to obesity (eight carriers of nonsynonymous mutations in 1,334 individuals with obesity vs. zero carriers of nonsynonymous mutations in 1,108 controls; nominal Fisher' exact two‐sided P < 0.005) in a crude meta‐analysis on all currently available data and this study. Limitations of our study include a relatively small sample size and the lack of additional family members for the nonsynonymous MRAP2 mutations.…”

Section: Discussionmentioning

confidence: 72%

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Decreased melanocortin‐4 receptor function conferred by an infrequent variant at the human melanocortin receptor accessory protein 2 gene

Schonnop

Kleinau

Herrfurth

et al. 2016

Obesity

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Section: Discussionmentioning

confidence: 72%

“…Additionally, among 363 children and adolescents with obesity who were screened for MRAP2 mutations, one carrier with a nonsynonymous mutation (p.Ala40Ser) was detected (10). In sum, these data suggested that variations in MRAP2 play a role in human obesity (8,10,11).…”

Section: Introductionmentioning

confidence: 83%

Decreased melanocortin‐4 receptor function conferred by an infrequent variant at the human melanocortin receptor accessory protein 2 gene

Schonnop

Kleinau

Herrfurth

et al. 2016

Obesity

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“…Copy number variation has important effects on gene transcription and translation, which usually results in dysfunction of protein products, even though coding sequence skipping can occur, ultimately leading to phenotypic variability [34,35]. CNV in the first two exons of LEPR gene had a significantly negative correlation with T2D susceptibility [12].…”

Section: Discussionmentioning

confidence: 99%

Divergent patterns of genic copy number variation in <i>KCNIP1</i> gene reveal risk locus of type 2 diabetes in Chinese population

Shi

Song

et al. 2018

Endocr J

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Abstract. Copy number variation (CNV) has emerged as another important genetic marker in addition to SNP for understanding etiology of complex disease. Kv channel interacting protein 1 (KCNIP1) is a Ca 2+ -dependent transcriptional modulator that contributes to the regulation of insulin secretion. Previous genome-wide CNV assay identified the KCNIP1 gene encompassing a CNV region, however, its further effect and risk rate on type 2 diabetes (T2D) have rarely been addressed, especially in Chinese population. The current study aims to detect and excavate genetic distribution profile of KCNIP1 CNV in Chinese T2D and control populations, and further to investigate the associations with clinical characteristics. Divergent patterns of the KCNIP1 CNV were identified (p < 0.01), in which the copy number gain was predominant in T2D, while the copy number normal accounted for the most in control group. Consistently, the individuals with copy number gain showed significant risk on T2D (OR = 4.550, p < 0.01). The KCNIP1 copy numbers presented significantly positive correlations with fasting plasma glucose and glycated hemoglobin in T2D. For OGTT test, the T2D patients with copy number gain had remarkably elevated glucose contents (60, 120, 180-min, p < 0.05 or p < 0.01) and diminished insulin levels (60, 120-min, p < 0.05) than those with copy number loss and normal, which suggested that the KCNIP1 CNV was correlated with the glucose and insulin action. This is the first CNV association study of the KCNIP1 gene in Chinese population, and these data indicated that KCNIP1 might function as a T2D-susceptibility gene whose dysregulation alters insulin production.

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“…By sequencing the coding regions and intron/exon boundaries of the gene, Asai et al also revealed 4 rare heterozygous variants in 4 severely obese children of which 1 (E24X) was clearly disruptive. In contrast to this, own CNV and mutation analysis in a cohort of 109 PWL patients only showed a limited involvement of copy number and sequence variation in SIM1 and MRAP2 in the PWL phenotype . More recently, Kasher et al also identified small deletions encompassing POU Class 3 Homeobox 2 ( POU3F2 ), and not SIM1 , at chromosome 6q in 10 individuals from 6 families with DD, ID, neonatal hypotonia, susceptibility to obesity and hyperphagia, characteristics resembling the PWL phenotype.…”

Section: Prader Willi Syndromementioning

confidence: 94%

Clinical, molecular genetics and therapeutic aspects of syndromic obesity

2018

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Obesity has become a major health problem worldwide. To date, more than 25 different syndromic forms of obesity are known in which one (monogenic) or multiple (polygenic) genes are involved. This review gives an overview of these forms and focuses more in detail on 6 syndromes: Prader Willi Syndrome and Prader Willi like phenotype, Bardet Biedl Syndrome, Alström Syndrome, Wilms tumor, Aniridia, Genitourinary malformations and mental Retardation syndrome and 16p11.2 (micro)deletions. Years of research provided plenty of information on the molecular genetics of these disorders and the obesity phenotype leading to a more individualized treatment of the symptoms, however, many questions still remain unanswered. As these obesity syndromes have different signs and symptoms in common, it makes it difficult to accurately diagnose patients which may result in inappropriate treatment of the disease. Therefore, the big challenge for clinicians and scientists is to more clearly differentiate all syndromic forms of obesity to provide conclusive genetic explanations and eventually deliver accurate genetic counseling and treatment. In addition, further delineation of the (functions of the) underlying genes with the use of array- or next-generation sequencing-based technology will be helpful to unravel the mechanisms of energy metabolism in the general population.

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Copy number variation (CNV) analysis and mutation analysis of the 6q14.1–6q16.3 genes SIM1 and MRAP2 in Prader Willi like patients

Cited by 25 publications

References 38 publications

Decreased melanocortin‐4 receptor function conferred by an infrequent variant at the human melanocortin receptor accessory protein 2 gene

Decreased melanocortin‐4 receptor function conferred by an infrequent variant at the human melanocortin receptor accessory protein 2 gene

Divergent patterns of genic copy number variation in <i>KCNIP1</i> gene reveal risk locus of type 2 diabetes in Chinese population

Clinical, molecular genetics and therapeutic aspects of syndromic obesity

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