High frequency of rare variants with a moderate-to-high predicted biological effect in protocadherin genes of extremely obese

Mariman, E.C.M.; Bouwman, Freek G.; Aller, Erik E. J. G.; Baak, Marleen A. van; Wang, Ping

doi:10.1007/s12263-014-0399-1

Cited by 11 publications

(15 citation statements)

References 33 publications

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“…Laminin α5 has had the gene variants shown to contribute to human body composition and weight [27] . A small subset of extremely obese humans were found to have variants in the laminin genes [28] . Future studies are needed that can address the mechanism including alteration in energy expenditure for the lean phenotype observed in Lama4 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

Laminin α4 Deficient Mice Exhibit Decreased Capacity for Adipose Tissue Expansion and Weight Gain

et al. 2014

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Obesity is a global epidemic that contributes to the increasing medical burdens related to type 2 diabetes, cardiovascular disease and cancer. A better understanding of the mechanisms regulating adipose tissue expansion could lead to therapeutics that eliminate or reduce obesity-associated morbidity and mortality. The extracellular matrix (ECM) has been shown to regulate the development and function of numerous tissues and organs. However, there is little understanding of its function in adipose tissue. In this manuscript we describe the role of laminin α4, a specialized ECM protein surrounding adipocytes, on weight gain and adipose tissue function. Adipose tissue accumulation, lipogenesis, and structure were examined in mice with a null mutation of the laminin α4 gene (Lama4−/ −) and compared to wild-type (Lama4+/+) control animals. Lama4−/ − mice exhibited reduced weight gain in response to both age and high fat diet. Interestingly, the mice had decreased adipose tissue mass and altered lipogenesis in a depot-specific manner. In particular, epididymal adipose tissue mass was specifically decreased in knock-out mice, and there was also a defect in lipogenesis in this depot as well. In contrast, no such differences were observed in subcutaneous adipose tissue at 14 weeks. The results suggest that laminin α4 influences adipose tissue structure and function in a depot-specific manner. Alterations in laminin composition offers insight into the roll the ECM potentially plays in modulating cellular behavior in adipose tissue expansion.

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Section: Discussionmentioning

confidence: 99%

Laminin α4 Deficient Mice Exhibit Decreased Capacity for Adipose Tissue Expansion and Weight Gain

et al. 2014

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“…In pigs, a PCDH7 homolog expressed differently in distinct adipocytes, suggesting that the expression level of PCDH7 may affect formation of different lipids [38] . The significant enrichment of rare variants in the protocadherin genes has been observed in a group of extremely obese individuals but not in the general population, indicating an association between rare variants in the protocadherin cluster genes and extreme obesity [39] . Protocadherin genes may also influence IMF by affecting eating.…”

Section: Discussionmentioning

confidence: 87%

Genome-wide association analysis reveals genetic loci and candidate genes associated with intramuscular fat in Duroc pigs

Wang¹,

Ding²,

Quan³

et al. 2017

Front. Agr. Sci. Eng.

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Intramuscular fat (IMF) is a major meat-quality trait in pigs. The content of IMF is directly associated with the taste and flavor of pork. As a complex trait, there could be multiple genes affecting IMF content in pork. Genomewide association study is a powerful tool to detect genomic regions associated with phenotypic variations. The objectives of the present study were to identify or refine the positions of genomic regions affecting IMF, and to characterize candidate genes and pathways that may influence this trait. Of note, we identified a significant region in longissium dorsi muscle in a Duroc pig population for IMF content with PorcineSNP60 v2 BeadChip. This region spans 1.24 Mb on chromosome 8 and had been identified as a quantitative trait locus for IMF in Pietrain, Large White, Landrace, and Leicoma pigs. In this region, eight SNPs were significantly associated with IMF content. Three genes proximal to these significant SNPs were considered candidate genes, including ZDHHC16, LOC102162218 and PCDH7. Our results confirm several previous findings and highlight several genes that may contribute to IMF variation in Duroc pigs.

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“…Subjects were selected as described before (24). In short, 561 obese persons attended the private obesity clinic CO-EUR (http:// www.co-eur.eu/), and from them we selected 30 ( DNA isolation and sequencing.…”

Section: Methodsmentioning

confidence: 99%

“…Notably, all of these genes are expressed in the hypothalamus, a section of the brain that is involved in regulating eating behavior. Recently, analysis of next-generation sequence data of 30 young adults with extreme obesity led to the detection of an enlarged frequency of rare variants in the clustered protocadherin genes on chromosome 5 (24). Those genes are involved in establishing neural networks, and some if not all of them are expressed in the hypothalamus.…”

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confidence: 99%

Extreme obesity is associated with variation in genes related to the circadian rhythm of food intake and hypothalamic signaling

Mariman

Bouwman

Aller

et al. 2015

Physiological Genomics

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The hypothalamus is important for regulation of energy intake. Mutations in genes involved in the function of the hypothalamus can lead to early-onset severe obesity. To look further into this, we have followed a strategy that allowed us to identify rare and common gene variants as candidates for the background of extreme obesity from a relatively small cohort. For that we focused on subjects with a well-selected phenotype and on a defined gene set and used a rich source of genetic data with stringent cut-off values. A list of 166 genes functionally related to the hypothalamus was generated. In those genes complete exome sequence data from 30 extreme obese subjects (60 genomes) were screened for novel rare indel, nonsense, and missense variants with a predicted negative impact on protein function. In addition, (moderately) common variants in those genes were analyzed for allelic association using the general population as reference (false discovery rate<0.05). Six novel rare deleterious missense variants were found in the genes for BAIAP3, NBEA, PRRC2A, RYR1, SIM1, and TRH, and a novel indel variant in LEPR. Common variants in the six genes for MBOAT4, NPC1, NPW, NUCB2, PER1, and PRRC2A showed significant allelic association with extreme obesity. Our findings underscore the complexity of the genetic background of extreme obesity involving rare and common variants of genes from defined metabolic and physiologic processes, in particular regulation of the circadian rhythm of food intake and hypothalamic signaling.

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High frequency of rare variants with a moderate-to-high predicted biological effect in protocadherin genes of extremely obese

Cited by 11 publications

References 33 publications

Laminin α4 Deficient Mice Exhibit Decreased Capacity for Adipose Tissue Expansion and Weight Gain

Laminin α4 Deficient Mice Exhibit Decreased Capacity for Adipose Tissue Expansion and Weight Gain

Genome-wide association analysis reveals genetic loci and candidate genes associated with intramuscular fat in Duroc pigs

Extreme obesity is associated with variation in genes related to the circadian rhythm of food intake and hypothalamic signaling

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