I am interested in human genetic disorders that impact the PR population, regulation of gene expression, and structure-function studies of proteins.
Setleis Syndrome Project
Setleis syndrome (MIM 227260) is an autosomal recessive disorder where patients exhibit bitemporal scar-like depressions, lateral deficiency of the eyebrows, double-rows or absent eyelashes and other facial abnormalities. The gene involved in Setleis Syndrome was mapped to 2q37.3 . Nonsense mutations in the TWIST2 gene in Puerto Rican (PR, Q119X) and Omani (Q65X) SS patients eliminated the entire bHLH domain plus the C terminus (Q65X), or the C terminus of the protein (Q119X). Expression analysis of skin fibroblast RNAs from PR Setleis Syndrome patients and normal controls using Affymetrix expression arrays revealed dramatic changes in the levels of mRNAs for proteins in the TGF beta/BMP signaling pathway, chemokines and cell adhesion proteins, as well as many others. Out of the top 287 differentially regulated probes (those with a fold change > 2.0 an a modified t value > 6.0), 189 were down-regulated, 98 were up-regulated and 162 genes were eligible for generating networks. RT-PCR analysis of mRNA levels of seventeen differentially regulated genes confirmed the microarray results when compared to the expression levels of three housekeeping genes. The Q119X protein localized to the nucleus while the Q65X protein is cytoplasmic. Gel mobility shift analysis of the two mutant proteins or nuclear extracts derived from skin fibroblasts demonstrate that binding to known Twist2 DNA target regions is affected. These findings show that homozygous nonsense mutations cause Setleis syndrome and bring new insights to the role of the TWIST2 gene in human development and disease.
Publications
Adam, W.; Cadilla, C.; Cueto, O.; Rodriguez, L.O 91980) Fluorescer -Enhanced Chemiluminescence of a Cyclic Peroxalate via Electron Exchange. J. Am. Chem. Soc., 1980, 102, 4802-4805
Cadilla CL, Harp J, Flanagan JM, Olins AL, Olins DE (1986) Preparation and characterization of soluble macronuclear chromatin from the hypotrich Euplotes eurystomus. Nucleic Acids Res 14(2):823-41.
Cadilla CL, Roberson AE, Harp J, Olins AL, Olins DE (1986) Subfractionation of soluble macronuclear chromatin and enrichment of specific genes as chromatin from Euplotes eurystomus. Nucleic Acids Res 14(21):8501-12.
Herrmann AL, Cadilla CL, Cacheiro LH, Carne AF, Olins DE (1987) An H1-like protein from the macronucleus of Euplotes eurystomus. Eur J Cell Biol 43(1):155-62.
M.H. Tindal, K.-L. Lee, K.R. Isham, C. Cadilla, and F.T. Kenney (1988). Structure of a multihormonally-regulated rat gene. Gene 71: 413-420.
C.L. Cadilla, K.R. Isham, K.L. Lee, L.-Y. Chan'g, A.C. Johnson, and F.T. Kenney (1992). Insulin increases transcription of rat gene 33 through cis-acting elements in 5'-flanking DNA. Gene 118: 223 -229.
F.L. Renaud, I. Colón, J. Lebrón, N. Ortiz, F. Rodríguez, and C. Cadilla (1995). A novel opioid mechanism seems to modulate phagocytosis in Tetrahymena. J. Euk. Microbiol. 42(3): 205-207.
S.L. Ramos-Martínez, I. Méndez, R. Delgado, and C.L. Cadilla (1996). Sequence analysis of the V1-V2 hypervariable region of the HIV-1 envelope gene from pediatric patients. PR Health Sci. J. 15:: 211-218.
J. Renta, C. L. Cadilla, M.E. Vega, G.V. Hillyer, C. Estrada, E. Jiménez, E. Abreu, I. Méndez, J. Gandía, and L. M. Meléndez-Guerrero (1997) Longitudinal studies on maternal HIV-1 variants by biological phenotyping, sequence analysis and viral load. Cellular and Molecular Biology (Noisy-le-grand)43(7):1097-114.
C L Cadilla, C R Lopez, S Garcia-Castiñeiras, D Valencia, JY Renta, E Rivera-Caragol, NJ Barrios, and P. J. Santiago Borrero (1998) Characterization of Hemoglobin Hotel Dieu in a Puerto Rican Adolescent. J. Ped. Hematol. Oncology, 20: 506-510.
F Antommattei-Pérez, T Rosado, CL Cadilla and J López-Garriga (1999) The cDNA-derived amino acid sequence of Hemoglobin I from Lucina pectinata. J. Protein Chemistry, 18, 831-836
P.A. Meléndez, N. Longo, B. D. Jiménez, and C. L. Cadilla (2000) Insulin-induced gene 33 mRNA expression in Chinese Hamster Ovary cells is insulin receptor-dependent. J. Cellular Biochem. 77(3):432-444.
A.Makkinje, D.A. Quinn, A.Chen, C. L.Cadilla, T. Force, J. Bonventre, and J.M. Kyriakis (2000) Gene 33/Mig-6; A transcriptionally-inducible Adapter Protein that binds GTP-Cdc-42 and activates SAPK/JNK. J. Biol.Chem. 275, 17838-17847.
T. Rosado-Ruiz, F. M. Antommattei-Pérez, F. M. Antommattei-Pérez, CL Cadilla and J.López-Garriga (2001) Expression and Purification of Recombinant Hemoglobin I from Lucina pectinata. Journal of Protein Chemistry 20 (4):311-315.
L.M. Meléndez-Guerrero, M. Arroyo, M.E. Vega, E. Jiménez, G.V. Hillyer, and C.L. Cadilla (2001) Genotypic and phenotypic characterization of HIV isolates from Puerto Rican Maternal-Infant Pairs reveal predominance of macrophage-tropic variants. Cell.Mol.Biol. vol.47, (Noisy-le-grand)47, N°6,Online paper DOI 10.1170/6, OL39-OL47.
L García-Fragoso, I García-García, A de la Vega, JY Renta and CL Cadilla (2002) Presence of the 5,10 methylenetetrahydrofolate reductase gene C677T mutation in Puerto Rican patients with neural tube defects. J. of Child Neurology 17:30–32.
Arroyo, M.A., Tien, H., Pagán, M., Swanstrom, R., Hillyer, G.V., Cadilla, C.L., and Meléndez-Guerrero, L.M. (2002). Virologic Factors for HIV-1 Vertical Transmission in Puerto Rico. AIDS Research and Human Retroviruses. 18(6):447-60.
I García-García, L García-Fragoso, J Renta, S Arce, and CL Cadilla (2002) Erythrocyte volume, folate levels, and the presence of a methylenetetrahydrofolate reductase polymorphism. PR Health Sci. J. 21:17-19.
E. Torres Mercado, J. Renta, Y. Rodríguez, J. López Garriga and C.L. Cadilla (2003) The cDNA –Derived
Amino Acid Sequence of Hemoglobin II from Lucina pectinata. J Protein Chemistry, 22(7-8): 683-90.
E. Collazo, R. Pietri, W. De Jesús, C, Ramos, R. G. León. C. L. Cadilla and J. López-Garriga (2004) Functional characterization of the purified Holo form of the Hemoglobin I from Lucina pectinata over-expressed in Escherichia coli. The Protein Journal 23 (4): 239-245,
Cordova A, Barrios NJ, Rivera E, Cadilla CL and Santiago Borrero PJ (2005) Poor response to desmopressin acetate (DDAVP) in children with Hermansky Pudlak Syndrome. Pediatric Blood and Cancer 43: 1-4.
RG Leon, H. Munier-Lehmann, O Barzu, V Baudin, J Lopez-Garriga, and CL Cadilla (2004) High-level
production of recombinant wild type and mutant sulfide-reactive hemoglobin I (HbI) from Lucina pectinata in Escherichia coli. Protein Expression and Purification, 38(2):184-95.
Pietri R, Granell L, Cruz A, De Jesus W, Lewis A, León R, Cadilla CL, and Lopez Garriga J (2005) Tyrosine
B10 and Heme-ligand interactions of Lucina pectinata Hemoglobin II: control of heme reactivity. Biochimica
et Biophysica Acta. 1747(2):195-203.
Santiago Borrero PJ, Y Rodríguez-Pérez, J Y. Renta, NJ Izquierdo, L del Fierro, D Muñoz, N López Molina, S Ramírez, G Mercado, I Ortíz, E Rivera-Caragol, RA Spritz, and C L Cadilla (2006) Genetic Testing for Oculocutaneous Albinism type 1 and 2 and Hermansky-Pudlak Syndrome type 1 and 3 mutations in Puerto Rico. J Invest Dermatol,. 126(1):85-90.
De Jesus-Bonilla W, Cruz A, Lewis A, Cerda J, Bacelo DE, Cadilla CL, Lopez-Garriga J. (2006) Hydrogen-bonding conformations of tyrosine B10 tailor the hemeprotein reactivity of ferryl species.J Biol Inorg Chem
11(3):334-42
Pietri R, León RG, Kiger L, Marden M, Granell LB, Cadilla CL and López Garriga J (2006) Hemoglobin I from Lucina pectinata: A model for distal heme-ligand binding Biochimica Biophysica Acta. 764(4):758-65.
Emanuelli A, Izquierdo JC, Berrocal MH, Garcia M, Cadilla C and Izquierdo NJ (2007) Foveal thickness and macular volume in patient with oculocutaneous albinism. Retina. 27(9):1227-30
Rivera Rivera LE, López-Garriga J and Cadilla CL (2008) Characterization of the full length mRNA coding for Lucina pectinata HbIII revealed an alternative polyadenylation site. Gene 410(1):122-8..
JA. Gavira, A Camara-Artigas, W de Jesús-Bonilla, J López-Garriga, A Lewis, R Pietri, S-R Yeh, CL Cadilla and JM García-Ruiz (2008) Structure and ligand selection of hemoglobin II from Lucina pectinata. J Biol Chem. In press. Jan 18; [Epub ahead of print].
García-Fragoso L, Leavitt G, García-García I, Renta J, Ayala MA, Cadilla CL (2008) MTHFR mutations in Puerto Rican children with isolated congenital heart disease and their mothers. Submitted to Congenital Heart Disease.
Ruaño G, Duconge J, Windemuth A, Cadilla CL, Kocherla M, Renta J, Richard S, Santiago-Borrero PJ. (2008) Physiogenomic Analysis of the Puerto Rican population. Submitted to Pharmacogenomics.
