Coding and noncoding expression patterns associated with rare obesity-related disorders: Prader–Willi and Alström syndromes

Advances in Genomics and Genetics, January 2015

25705109

Merlin G Butler, Kun Wang, Jan D Marshall, Jürgen K Naggert, Jasmine A Rethmeyer, Sumedha S Gunewardena, Ann M Manzardo

Obesity is accompanied by hyperphagia in several classical genetic obesity-related syndromes that are rare, including Prader-Willi syndrome (PWS) and Alström syndrome (ALMS). We compared coding and noncoding gene expression in adult males with PWS, ALMS, and nonsyndromic obesity relative to nonobese males using readily available lymphoblastoid cells to identify disease-specific molecular patterns and disturbed mechanisms in obesity. We found 231 genes upregulated in ALMS compared with nonobese males, but no genes were found to be upregulated in obese or PWS males and 124 genes were downregulated in ALMS. The metallothionein gene (MT1X) was significantly downregulated in ALMS, in common with obese males. Only the complex SNRPN locus was disturbed (downregulated) in PWS along with several downregulated small nucleolar RNAs (snoRNAs) in the 15q11-q13 region (SNORD116, SNORD109B, SNORD109A, SNORD107). Eleven upregulated and ten downregulated snoRNAs targeting multiple genes impacting rRNA processing, developmental pathways, and associated diseases were found in ALMS. Fifty-two miRNAs associated with multiple, overlapping gene expression disturbances were upregulated in ALMS, and four were shared with obese males but not PWS males. For example, seven passenger strand microRNAs (miRNAs) (miR-93*, miR-373*, miR-29b-2*, miR-30c-1*, miR27a*, miR27b*, and miR-149*) were disturbed in association with six separate downregulated target genes (CD68, FAM102A, MXI1, MYO1D, TP53INP1, and ZRANB1). Cell cycle (eg, PPP3CA), transcription (eg, POLE2), and development may be impacted by upregulated genes in ALMS, while downregulated genes were found to be involved with metabolic processes (eg, FABP3), immune responses (eg, IL32), and cell signaling (eg, IL1B). The high number of gene and noncoding RNA disturbances in ALMS contrast with observations in PWS and males with nonsyndromic obesity and may reflect the progressing multiorgan pathology of the ALMS disease process.