👤 Eric Kenneth Parkinson

Childhood obesity is a global concern and has both nutritional and genetic causative factors. One of the most common monogenic causes of obesity is heterozygous mutations in the Melanocortin 4 receptor (MC4R), which are found in 5.7-8.6% of individuals with early-onset obesity. We report, the effect of semaglutide, a long-acting glucagon-like peptide (GLP-1) analogue, in the treatment of severe obesity in an adolescent boy with a heterozygous mutation in MC4R. A 13-year-old boy with a history of excessive weight gain since infancy was referred to the specialised weight management team. He was born at full term with a birth weight of 3.57 kg (50th centile), but his weight consistently exceeded the 99.6th percentile after the age of 1 year. At the age of 5 years, he was diagnosed with autism spectrum disorder (ASD). Diagnostic investigations revealed insulin resistance and dyslipidaemia, while genetic testing confirmed a heterozygous mutation in MC4R (E61K), inherited from his mother. Managing his condition was challenging due to his rapid weight gain, needle phobia, and behavioural difficulties. Despite intense multidisciplinary lifestyle interventions, he continued to gain weight, reaching a peak weight of 187.5 kg (+16.65 standard deviation score [SDS]), body mass index (BMI) of 56.9 kg/m2 (+4.19 SDS), and body fat of 63.9% at the age of 13 years. Due to severe ASD and needle phobia, he was not keen on daily GLP-1 injections. He was commenced on semaglutide subcutaneous injection at a dose of 0.25 mg weekly, gradually increasing to the maximum dose of 1 mg weekly. Over the course of 12 weeks, his BMI decreased to 52.2 kg/m2 (+4.08 SDS) and weight dropped to 176.8 kg (+14.76 SDS, body fat: 52.7%). At the 3-month and 12-month reviews post-treatment, he achieved weight loss of 5.7% and 11%, respectively. The quality of life questionnaire showed improved scores from 35.95 to 60.36 at 12-month review, indicating enhanced well-being. The continuous glucose monitor demonstrated an improvement in time in range. Semaglutide was approved by the US Food and Drug Administration (FDA) for weight management in adolescents aged 12 years and above in December 2022. A recent case series underscored the benefits of therapy with liraglutide, a short-acting GLP-1 analogue, in rare genetic cases of early-onset obesity. To our knowledge, this is the first case report to highlight the efficacy and safety of semaglutide in an adolescent with heterozygous MC4R mutation. Semaglutide could be a potential treatment option for monogenic obesity and will benefit from further research. Show less

Directed evolution is a powerful approach for engineering proteins with enhanced affinity or specificity for a ligand of interest but typically requires many rounds of screening/library mutagenesis to obtain mutants with desired properties. Furthermore, mutant libraries generally only cover a small fraction of the available sequence space. Here, for the first time, we use ordinal regression to model protein sequence data generated through successive rounds of sorting and amplification of a protein-ligand system. We show that the ordinal regression model trained on only two sorts successfully predicts chromodomain CBX1 mutants that would have stronger binding affinity with the H3K9me3 peptide. Furthermore, we can extract the predictive features using contextual regression, a method to interpret nonlinear models, which successfully guides identification of strong binders not even present in the original library. We have demonstrated the power of this approach by experimentally confirming that we were able to achieve the same improvement in binding affinity previously achieved through a more laborious directed evolution process. This study presents an approach that reduces the number of rounds of selection required to isolate strong binders and facilitates the identification of strong binders not present in the original library. Show less

We report changes in the genomic landscape in the development of head and neck squamous cell carcinomas HNSCC from potentially premalignant lesions (PPOLS) to malignancy and lymph node metastases. Likely pathological mutations predominantly involved a relatively small set of genes reported previously (TP53, KMT2D, CDKN2A, PIK3CA, NOTCH1 and FAT1) but also other predicted cancer drivers (MGA, PABPC3, NR4A2, NCOR1 and MACF1). Notably, all these mutations arise early and are present in PPOLs. The most frequent genetic changes, which follow acquisition of immortality and loss of senescence, are of consistent somatic copy number alterations (SCNAs) involving chromosomal regions enriched for genes in known and previously unreported cancer-related pathways. We mapped the evolution of SCNAs in HNSCC progression. One of the earliest SCNAs involved deletions of CSMD1 (8p23.2). CSMD1 deletions or promoter hypermethylation were present in all of the immortal PPOLs and occurred at high frequency in the immortal HNSCC cell lines. Modulation of CSMD1 in cell lines revealed significant suppression of proliferation and invasion by forced expression, and significant stimulation of invasion by knockdown of expression. Known cancer drivers NOTCH1, PPP6C, RAC1, EIF4G1, PIK3CA showed significant increase in frequency of SCNA in transition from PPOLs to HNSCC that correlated with their expression. In the later stages of progression, HNSCC with and without nodal metastases showed some clear differences including high copy number gains of CCND1, hsa-miR-548k and TP63 in the metastases group. Show less