In order to add to the pool of high-impact variants, Rhythm is undertaking a comprehensive effort to screen and classify new and uncharacterized variants in the MC4R pathway, using both computational models for assessing variants and biochemical analysis of variants in POMC, PCSK1
, and LEPR to assess functional impact.
GLP-1 isa30-amino acid product of the preproglucagon gene, and GLP-1 is converted by proprotein convertase 1 (PC1/3), which is encoded by the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene [13-15].
qRT-PCR was used to examine the relative mRNA levels of preproglucagon and PCSK1 in the jejunal and ileal segments.
proSAAS, a protein encoded by the mouse gene Pcsk1
and precursor to 5 different neuropeptides (big SAAS, little SAAS, PEN, big LEN, and little LEN), seems to act as an inhibitor of PC1 (25), and genetic overproduction of proSAAS leads to late-onset obesity in mice (26).
The diagnosis of PC1/3 deficiency was established by the mutation analysis of PCSK1
Mbikay, "60 years of POMC: from the prohormone theory to pro-opiomelanocortin and to proprotein convertases (PCSK1
to PCSK9)," Journal of Molecular Endocrinology, vol.
 found that the correlation between the G allele of PCSK1
gene (rs6232) and obesity was significant only in adult class III obesity.
. Proprotein/neuroendocrine convertase deficiency, caused by rare mutations in PCSK1
gene, has been associated with obesity, severe malabsorptive diarrhea, and certain endocrine abnormalities .
At the other end of the spectrum lies the case of extreme obesity, mostly since birth, and here again germ line transmission in genetic alterations was noted in leptin (LEP), leptin receptor (LEPR), proopiomelanocortin (POMC), prohormone convertase 1 (PCSK1
), melanocortin 4 receptor (MC4R), single-minded homolog 1 (SIM1), brain-derived neurotrophic factor (BDNF), and its receptor TrkB coded by neurotrophic tyrosine kinase receptor type 2 gene (NTRK2) reviewed in .
In particular, cathepsin B, matrix metalloproteases, and furin-related PCSK1
are likely to be expressed on the surface of macrophages and recognize the hallmark residues remaining or acquired in FIPV S1/S2 cleavage site (30).
The other gene, PCSK1
, encodes an enzyme that helps make insulin.
Professor Philippe Froguel said: "This is the first time we have found a strong link between common mutations and common obesity in the PCSK1