Extended Data Sets and Supplemental Materials
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Item Sex differences in severity of metabolic complications in patients with congenital generalized lipodystrophy(2022-12-15) Lima, Josivan Gomes; Nobrega, Lucia Helena Coelho; Baracho, Maria de Fatima Paiva; Lima, Lucas Nobrega; de Melo Campos, Julliane Tamara Araújo; Lima, Debora Nobrega; Lima, Grayce Ellen Paiva; Fernandes, Virginia Oliveira; Montenegro Júnior, Renan Magalhães; Garg, AbhimanyuCONTEXT: Previous data support a higher prevalence of metabolic complications in females affected with familial partial lipodystrophy than in males. However, whether there are any sex differences in the prevalence and severity of metabolic complications among patients with congenital generalized lipodystrophy (CGL) remains unclear. OBJECTIVES: To compare prevalence of metabolic complications and metabolic parameters between males and females with CGL. DESIGN: A retrospective, cross-sectional comparison. SETTINGS: Patients from two tertiary referral centers from Northeastern Brazil - Universidade Federal do Rio Grande do Norte, Natal, and Universidade Federal do Ceará, Fortaleza. PATIENTS: A total of 44 females (age 2-51 years) and 28 males (age 5-46 years) with CGL. Twenty-six (7 M, 19 F) had genotypically confirmed CGL type 1, 43 (20 M, 23 F) had CGL type 2, and 3 patients were not genotyped. MAIN OUTCOME MEASURES: Prevalence of diabetes mellitus and hypertriglyceridemia, and metabolic variables. RESULTS: Females with CGL, as compared to males, had significantly increased prevalence of diabetes (82% vs. 54%; p<0.01) and hypertriglyceridemia (91% vs. 71%; p=0.05); and had higher median fasting serum triglycerides levels (383 vs. 221 mg/dL; p=0.01), but not statistically significantly higher median hemoglobin A1c (7.9% vs. 6.5%; p=0.37) and fasting serum glucose levels (138 vs. 89 mg/dL; p=0.06). CONCLUSIONS: Compared to males, females with CGL have increased prevalence of metabolic complications, such as diabetes and hypertriglyceridemia, suggesting need for close monitoring of metabolic parameters, and early and aggressive intervention among them.Item Phenotypic differences among Familial Partial Lipodystrophy due to LMNA or PPARG variants(2022-08-05) Vasandani, Chandna; Li, Xilong; Sekizkardes, Hilal; Brown, Rebecca J.; Garg, AbhimanyuCONTEXT: Despite several reports of familial partial lipodystrophy, type 2 (FPLD2) due to heterozygous LMNA variants and FPLD3 due to PPARG variants, the phenotypic differences among them remain unclear. OBJECTIVES: To compare the body fat distribution, metabolic parameters, and prevalence of metabolic complications between FPLD3 and FPLD2. DESIGN: A retrospective, cross-sectional comparison. SETTINGS: Patients from two tertiary referral centers - UT Southwestern Medical Center and the National Institute of Diabetes and Digestive and Kidney Diseases. PATIENTS: A total of196 females and 59 males with FPLD2 (age 2-86 years) and 28 females and 4 males with FPLD3 (age 9-72 years). MAIN OUTCOME MEASURES: Skinfold thickness, regional body fat measurements by dual energy X-ray absorptiometry (DXA), metabolic variables and prevalence of diabetes mellitus and hypertriglyceridemia. RESULTS: Compared to FPLD2 subjects, FPLD3 subjects had significantly increased prevalence of hypertriglyceridemia (66% vs. 84%) and diabetes (44% vs. 72%); and had higher median fasting serum triglycerides (208 vs. 255 mg/dL), and hemoglobin A1c (5.7% vs. 7.0%). Compared to FPLD2 subjects, FPLD3 subjects also had significantly higher median upper limb fat (20% vs. 27%) and lower limb fat (16% vs. 21%) on DXA and increased median skinfold thickness at the anterior thigh (5.8 vs.11.3 mm); calf (4 vs. 6 mm); triceps (5.5 vs. 7.5 mm); and biceps (4.3 vs. 6.8 mm). CONCLUSIONS: Compared to FPLD2, FPLD3 subjects have milder lipodystrophy but develop more severe metabolic complications, suggesting that remaining adipose tissue in FPLD3 subjects may be dysfunctional or those with mild metabolic disease are under-recognized.Item High Co-Expression of the Ghrelin and LEAP2 Receptor GHSR with Pancreatic Polypeptide in Mouse and Human Islets(2021-07-09) Gupta, Deepali; Dowsett, Georgina K. C.; Mani, Bharath K.; Shankar, Kripa; Osborne-Lawrence, Sherri; Metzger, Nathan P.; Lam, Brian Y. H.; Yeo, Giles S. H.; Zigman, Jeffrey M.Islets represent an important site of direct action of the hormone ghrelin, with expression of the ghrelin receptor (growth hormone secretagogue receptor; GHSR) having been localized variably to alpha-cells, beta-cells, and/or somatostatin (SST)-secreting delta-cells. To our knowledge, GHSR expression by pancreatic polypeptide (PP)-expressing gamma-cells has not been specifically investigated. Here, histochemical analyses of Ghsr-IRES-Cre X Cre-dependent ROSA26-YFP reporter mice showed 85% of GHSR-expressing islet cells co-express PP, 50% co-express SST, and 47% co-express PP + SST. Analysis of single-cell transcriptomic data from mouse pancreas revealed 95% of Ghsr-expressing cells co-express Ppy, 100% co-express Sst, and 95% co-express Ppy + Sst. This expression was restricted to gamma-cell and delta-cell clusters. Analysis of several single-cell human pancreatic transcriptome datasets revealed 59% of GHSR-expressing cells co-express PPY, 95% co-express SST, and 57% co-express PPY + SST. This expression was prominent in delta-cell and beta-cell clusters, also occurring in other clusters including gamma-cells and alpha-cells. GHSR expression levels were upregulated by type 2 diabetes mellitus in beta-cells. In mice, plasma PP positively correlated with fat mass and with plasma levels of the endogenous GHSR antagonist/inverse agonist LEAP2. Plasma PP also elevated upon LEAP2 and synthetic GHSR antagonist administration. These data suggest that in addition to delta-cells, beta-cells, and alpha-cells, PP-expressing pancreatic cells likely represent important direct targets for LEAP2 and/or ghrelin in both mice and humans.Item A Novel Autosomal Recessive, Progeroid Syndrome with Short Stature, Mandibular Hypoplasia, Osteoporosis and Short Eyebrows Due to a Homozygous Mutation in PRRT3(2019-09-18) Garg, Abhimanyu; El-Shanti, Hatem; Xing, Chao; Zhou, Zhengyang; Abujbara, Mousa; Al-Rashed, Khadeja; El-Khateeb, Mohammed; Ajlouni, Kamel; Agarwal, Anil K.CONTEXT: Despite considerable progress in elucidating the molecular basis of various progeroid syndromes, some rare patients remain unexplained. OBJECTIVE: To elucidate molecular genetic basis of a novel autosomal recessive progeroid syndrome. PARTICIPANTS: A 21-year-old male and his 17-year-old sister with short stature, mandibular hypoplasia, pointed nose, shrill voice, severe osteoporosis, and short eyebrows; and their unaffected siblings and parents belonging to a consanguineous Arab family. RESULTS: Using exome and Sanger sequencing, we report a novel homozygous p.Glu394Lys disease-causing mutation in proline rich transmembrane protein 3 (PRRT3). PRRT3 belongs to the family of proline-rich proteins containing several repeats of a short proline-rich sequence but its function remains to be determined. Preliminary observations showing co-localization of Prrt3 and synaptophysin support its role in vesicle exocytosis. Consistent with the highest mRNA expression of PRRT3 in the pituitary, both the patients had mild growth hormone deficiency but had near normal reproductive development. CONCLUSIONS: We conclude that the homozygous p.Glu394Lys mutation in PRRT3 causes a novel autosomal recessive, progeroid syndrome with short stature, mandibular hypoplasia, osteoporosis, short eyebrows and mild GH deficiency. Our findings extend the spectrum of progeroid syndromes and elucidate important functions of PRRT3 in human biology including secretion of growth hormone from the pituitary.Item Molecular Characterization of Familial Hypercholesterolemia in a North American Cohort(2019-06-07) Garg, Abhimanyu; Fazio, Sergio; Duell, P. Barton; Baass, Alexis; Udata, Chandrasekhar; Joh, Tenshang; Riel, Tom; Sirota, Marina; Dettling, Danielle; Liang, Hong; Garzone, Pamela D.; Gumbiner, Barry; Wan, HongBACKGROUND: Familial hypercholesterolemia (FH) confers a very high risk of premature cardiovascular disease and is commonly caused by mutations in LDLR, APOB, or PCSK9 and very rarely in LDLRAP1. OBJECTIVE: To determine the prevalence of pathogenic mutations in the LDLR, APOB, and PCSK9 in a cohort of subjects who met Simon Broome criteria for FH, and compare the clinical characteristics of mutation-positive and –negative subjects. METHODS: 93 men and 107 women aged 19–80 years from lipid clinics in the United States and Canada participated. Demographic and historical data were collected, physical examination performed, and serum lipids/lipoproteins analyzed. Targeted sequencing analyses of LDLR and PCSK9 coding regions and exon 26 of APOB were performed, followed by detection of LDLR deletions and duplications. RESULTS: Disease-causing LDLR and APOB variants were identified in 114 and 6 subjects, respectively. Of the 58 LDLR variants, 8 were novel mutations. Compared with mutation-positive subjects, mutation-negative subjects were older (mean: 49 years versus 57 years, respectively) and had a higher proportion of African-Americans (1% versus 12.5%), higher prevalence of hypertension (21% versus 46%), and higher serum triglycerides (median: 86 mg/dL versus 122 mg/dL) levels. CONCLUSION: LDLR mutations were the most common cause of heterozygous FH in this North American cohort. A strikingly high proportion of FH subjects (40%) lacked mutations in known culprit genes. Identification of underlying genetic and environmental factors in mutation-negative patients is important to further our understanding of the metabolic basis of FH and other forms of severe hypercholesterolemia.Item Oligonucleotide Primer Sequences(2018-09-06) Zigman, Jeffrey M.; Rodriguez, Juan A.