Griscelli syndrome-type 2 in twin siblings: case report and update on RAB27A human mutations and gene structure

Griscelli syndrome (GS) is a rare autosomal recessive disorder caused by mutation in the MYO5A (GS1, Elejalde), RAB27A (GS2) or MLPH (GS3) genes. Typical features of all three subtypes of this disease include pigmentary dilution of the hair and skin and silvery-gray hair. Whereas the GS3 phenotype is restricted to the pigmentation dysfunction, GS1 patients also show primary neurological impairment and GS2 patients have severe immunological deficiencies that lead to recurrent infections and hemophagocytic syndrome. We report here the diagnosis of GS2 in 3-year-old twin siblings, with silvery-gray hair, immunodeficiency, hepatosplenomegaly and secondary severe neurological symptoms that culminated in multiple organ failure and death. Light microscopy examination of the hair showed large, irregular clumps of pigments characteristic of GS. A homozygous nonsense mutation, C-T transition (c.550C>T), in the coding region of the RAB27A gene, which leads to a premature stop codon and prediction of a truncated protein (R184X), was found. In patient mononuclear cells, RAB27A mRNA levels were the same as in cells from the parents, but no protein was detected. In addition to the case report, we also present an updated summary on the exon/intron organization of the human RAB27A gene, a literature review of GS2 cases, and a complete list of the human mutations currently reported in this gene. Finally, we propose a flow chart to guide the early diagnosis of the GS subtypes and Chédiak-Higashi syndrome.FAPESPCNPq(FAEPA) Fundação de Apoio ao Ensino, Pesquisa e Assistência do Hospital das Clínicas da Faculdade de Medicina de Ribeirão PretoCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES

T Allele Of -344c/t Polymorphism In Aldosterone Synthase Gene Is Not Associated With Resistant Hypertension

Resistant hypertension (RH) is the maintenance of elevated blood pressure concurrent with the use of three different anti-hypertensive drugs, one of which is a diuretic. The Renin-Angiotensin-Aldosterone System plays a major role in volume-dependent hypertension. Therefore, its components are interesting targets for genetic association studies. This work focused on the -344 C/T polymorphism in the CYP11b2 gene, which encodes aldosterone synthase. This work evaluates the association between T allele and resistance to anti-hypertensive treatment. Genotyping analysis included 88 subjects with RH, 142 who were responsive to anti-hypertensive treatment and 110 subjects as a control group. Plasmatic concentrations of aldosterone, renin and cortisol, carotid intima-media thickness and carotid-femoral pulse wave velocity were assessed in a smaller subset of hypertensive patients. An association was found between T allele and hypertension (P<0.005), but there was no difference in allele frequencies between both hypertensive groups. There was no difference in plasmatic parameters either, in remodeling indicators between the genotypic groups.322159162Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr JL, Jones DW, Materson BJ, Oparil S, Wright Jr JT, Roccella EJ. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 2003289: 2560-2572Gaddam, K.K., Nishizaka, M.K., Pratt-Ubunama, M.N., Pimenta, E., Aban, I., Oparif, S., Calhoun, D.A., Characterization of resistant hypertension: Association between resistant hypertension, alcosterone, and persistent intravascular volume expansion (2008) Arch Intern Med, 168, pp. 1159-1164Freel, E.M., Ingram, M., Friel, E.C., Fraser, R., Brown, M., Samani, N.J., Caulfield, M., Connell, J.M., Phenotypic consequences of variation across the aldosterone synthase and 11-beta hydroxylase locus in a hypertensive cohort: Data from the MRC BRIGHT Study (2007) Clin Endocrinol (Oxf), 67, pp. 832-838White, P.C., Slutsker, L., Haplotype analysis of CYP11B2 (1995) Endocr Res, 21, pp. 437-442Freitas, S.R., Cabello, P.H., Moura-Neto, R.S., Dolinsky, L.C., Lima, A.B., Barros, M., Bittencourt, I., Cordovil, I.L., Analysis of renin-angiotensin-aldosterone system gene polymorphisms in resistant hypertension (2007) Braz J Med Biol Res, 40, pp. 309-316Hilgers, K.F., Schmidt, B.M., Gene variants of aldosterone synthase and hypertension (2005) J Hypertens, 23, pp. 1957-1959Davies, E., Holloway, C.D., Ingram, M.C., Inglis, G.C., Friel, E.C., Morrison, C., Anderson, N.H., Connell, J.M., Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2 (1999) Hypertension, 33, pp. 703-707Iwai, N., Kajimoto, K., Tomoike, H., Takashima, N., Polymorphism of CYP11B2 determines salt sensitivity in Japanese (2007) Hypertension, 49, pp. 825-831Park, S., Kim, J.B., Shim, C.Y., Ko, Y.G., Choi, D., Jang, Y., Chung, N., The influence of serum aldosterone and the aldosterone-renin ratio on pulse wave velocity in hypertensive patients (2007) J Hypertens, 25, pp. 1279-1283Holaj, R., Zelinka, T., Wichterle, D., Petrak, O., Strauch, B., Widimsky Jr, J., Increased intima-media thickness of the common carotid artery in primary aldosteronism in comparison with essential hypertension (2007) J Hypertens, 25, pp. 1451-1457Boutouyrie, P., Tropeano, A.I., Asmar, R., Gautier, I., Benetos, A., Lacolley, P., Laurent, S., Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: A longitudinal study (2002) Hypertension, 39, pp. 10-15Laurent, S., Cockcroft, J., Van Bortel, L., Boutouyrie, P., Giannattasio, C., Hayoz, D., Pannier, B., Struijker-Boudier, H., Expert consensus document on arterial stiffness: Methodological issues and clinical applications (2006) Eur Heart J, 27, pp. 2588-2605Pitt, B., Zannad, F., Remme, W.J., Cody, R., Castaigne, A., Perez, A., Palensky, J., Wittes, J., The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators (1999) N Engl J Med, 341, pp. 709-717Pitt, B., Remme, W., Zannad, F., Neaton, J., Martinez, F., Roniker, B., Bittman, R., Gatlin, M., Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction (2003) N Engl J Med, 348, pp. 1309-1321Schiffrin, E.L., Effects of aldosterone on the vasculature (2006) Hypertension, 47, pp. 312-318Taylor, D.W., Sackett, D.L., Haynes, R.B., Johnson, A.L., Gibson, E.S., Roberts, R.S., Compliance with antihypertensive drug therapy (1978) Ann NY Acad Sci, 304, pp. 390-403Cittadino, M., Goncalves de Sousa, M., Ugar-Toledo, J.C., Rocha, J.C., Tanus-Santos, J.E., Moreno Jr, H., Biochemical endothelial markers and cardiovascular remodeling in refractory arterial hypertension (2003) Clin Exp Hypertens, 25, pp. 25-3