Poster Presentation

CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome
and affect plasma insulin and platelet activation

Fatemehsadat Esteghamat, James S. Broughton, Emily Smith, Rebecca Cardone, Tarun Tyagi, Mateus Guerra, András Szabó, Nelson Ugwu, Mitra V. Mani, Bani Azari, Gerald Kayingo, Sunny Chung, Mohsen Fathzadeh,
Ephraim Weiss, Jeffrey Bender, Shrikant Mane, Richard P. Lifton, Adebowale Adeniran, Michael H. Nathanson, Fred S. Gorelick, John Hwa, Miklós Sahin-Tóth, Renata Belfort-DeAguiar, Richard G. Kibbey, and Arya Mani
Introduction Methods and Results (cont.) Methods and Results (cont.)

• Metabolic syndrome is a complex disease that primarily relates to CELA2A Protein Expression CELA2A Effect on Platelet Activation A Lumi-Aggregometer
b
insulin resistance and leads to an increased risk of type 2 diabetes Fig. 3a and b: measured effect of WT and mutant CELA2A on human platelet
Western blot aggregation. b
and early onset coronary artery disease (CAD)1
• Metabolic syndrome in people with CAD may be caused by single- analysis showed Fig. 7a and b:
gene mutations2,3 (a) CELA2A Platelet
• CELA2A, a chymotrypsin-like elastase family member 2A encoded absence in the aggregation
by CELA2A, is primarily known as an exocrine pancreatic elastase4,5 p.D121N, (a) increased
• A1AT is a protease inhibitor and protects tissues from enzymes, p. T70M, and splice site variants and (b) CELA2A + A1AT complex after treatment
such as elastases6 absence in p.D121N, p. T70M, and splice site variants and a small with p.D121N,
• The effects of CELA2A outside of the pancreas are unknown. complex in the p.L85M-CELA2A variant. (b) p.L85M, or
CELA2A Effect on Insulin Levels ELISA kits were used to measure p.T70M compared to WT-CELA2A
insulin, C-peptide, and glucagon levels after a meal
Objective / Central Hypothesis a b
Conclusions
This paper explores the effects of CELA2A mutations on metabolic
• Identification of single-gene variants
function outside of the pancreas through in vitro and in vivo studies.
underlying metabolic syndrome and CAD
and characterization of disease relevant
Methods and Results functions.
• CELA2A regulates insulin and restrains
Participants Multiplex kindred (CAD-2001) with 25 affected B platelet aggregation.
individuals with metabolic syndrome and early onset. The familiar
clustering and pattern of inheritance were consistent with highly Fig. 4a and b: Direct parallel correlation of CELA2A plasma levels to (a) • Near perfect correlation between plasma
insulin and (b) C-peptide postprandially. CELA2A and insulin levels suggests
penetrant, autosomal dominant inheritance (Fig. 1). They also
a b CELA2A acts as insulinotropic peptide.
examined 30 other index cases.
• WT-CELA2A limits the activation of
platelets through proteolytic degradation,
but mutant CELA2A promotes
hyperactivation and aggregation of platelets.
Future Directions
Fig. 5a and b: Glucagon showed an inverse relationship with plasma
• CELA2A, as a systemic protein, shows potential for therapeutic
Fig. 1: Pedigree of CAD-2001. CELA2A postprandially.
application for treatment of atherosclerosis, thrombosis, and
Whole-Exome Sequencing Sequencing revealed 3 missense CELA2A Effect on Insulin Secretion through Voltage-gated Ca2+
impaired glucose tolerance.
mutations (p.D121N, p.L85M, and p.T70M) and one splice site Channels Rat insulinoma cell lines treated with WT CELA2A showed
activation of protein kinase A and higher levels of intracellular Ca2+
mutation (c.639+1G>C) in CELA2A. Pathogenicity determined by
compared to p.D121N-CELA2A mutant. References
bioinformatics.
CELA2A Effect on Insulin Degradation 1. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. The Lancet. 2005 April 16-22; 365(946B):
1415–1428.
Fig. 6a and b: After 48 hours, (a) insulin levels in rat islet cells treated 2. Mani A. et al. LRP6 mutation in a family with early coronary disease and metabolic risk factors. Science.
with WT-CELA2A were a b 2007; 315: 1278–1282.
3. Keramati AR. et al. A form of the metabolic syndrome associated with mutations in DYRK1B. N. Engl.
lower than cells treated J. Med. 2014; 370; 1909–1919.
with p.D121N-CELA2A 4. Szepessy E, Sahin-Toth M. Inactivity of recombinant ELA2B provides a new example of evolutionary
elastase silencing in humans. Pancreatology. 2006; 6: 117–122.
Fig. 2: Shared haplotype from CAD-2001 showing shared and (b) WT-CELA2A, not 5. Largman C, Brodrick JW, Geokas MC. Purification and characterization of two human pancreatic
chromosomal interval flanked by 2 SNPs containing a missense mutants, cause insulin elastases. Biochemistry. 1976; 15: 2491–2500.
6. Brantly M, Nukiwa T, Crystal RG. Molecular basis of alpha-1-antitrypsin deficiency. Am J Med. 1988;
mutation in exon 6 of CELA2A (p.D121N). Sequencing of all 30 fragmentation. 84: 13–31.
7. Oleksyszyn J, Powers JC. Irreversible inhibition of serine proteases by peptide derivatives of (alpha-
index cases were not pictured. aminoalkyl)phosphonate diphenyl esters. Biochemistry. 1991; 30: 485–493.

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CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome

and affect plasma insulin and platelet activation

Introduction Methods and Results (cont.) Methods and Results (cont.)

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