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

Area of Science:

• Genetics
• Molecular Biology
• Endocrinology

Background:

• Obesity, particularly hyperphagia, is a hallmark of rare genetic syndromes like Prader-Willi syndrome (PWS) and Alström syndrome (ALMS).
• Understanding the molecular underpinnings of these conditions is crucial for identifying disease-specific mechanisms.

Purpose of the Study:

• To compare gene and noncoding RNA expression in adult males with PWS, ALMS, and nonsyndromic obesity against nonobese controls.
• To identify disease-specific molecular patterns and disturbed mechanisms in obesity using lymphoblastoid cells.

Main Methods:

• Gene expression profiling of coding and noncoding RNAs in lymphoblastoid cells.
• Comparative analysis between PWS, ALMS, nonsyndromic obesity, and nonobese male cohorts.

Main Results:

• Alström syndrome (ALMS) exhibited significant upregulation (231 genes) and downregulation (124 genes) of gene expression.
• Metallothionein gene (MT1X) was downregulated in ALMS and obese males; Prader-Willi syndrome (PWS) showed disturbances in the SNRPN locus and specific snoRNAs.
• ALMS displayed numerous upregulated and downregulated small nucleolar RNAs (snoRNAs) and microRNAs (miRNAs), impacting rRNA processing, development, and metabolic pathways, with some shared with nonsyndromic obesity.

Conclusions:

• Alström syndrome (ALMS) presents a distinct and extensive profile of molecular disturbances compared to Prader-Willi syndrome (PWS) and nonsyndromic obesity.
• The identified gene and noncoding RNA alterations in ALMS likely contribute to its progressive multiorgan pathology.