Weiss R E, Sunthornthepvarakul T, Angkeow P, Marcus-Bagley D, Cox N, Alper C A, Refetoff S
Department of Medicine, J. P. Kennedy, Jr., Mental Retardation Research Center, University of Chicago 60637.
J Clin Endocrinol Metab. 1995 Jan;80(1):116-21. doi: 10.1210/jcem.80.1.7829599.
Familial dysalbuminemic hyperthyroxinemia (FDH) is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasians. Transmitted as an autosomal dominant trait, it is always associated with high serum total T4 (TT4) and more rarely with elevated total T3 (TT3) and/or rT3 (TrT3) concentrations. Free T4, by dialysis, and TSH levels are normal, suggesting the presence of a T4-binding protein abnormality. The abnormal serum T4 carrier shares some physical and immunological properties with albumin, suggesting that it may be albumin itself. Here we show linkage between FDH and the albumin gene in a large Amish family of Swiss descent, using as markers a SacI polymorphism in the coding sequence of the albumin gene and the group-specific component (Gc) gene, located less than 1 centimorgan from the albumin gene. Blood samples were obtained from 160 members of this kindred, and 22 had FDH identified by the pattern of T4 binding to serum proteins separated by isoelectric focusing. Serum TT4 values were above the normal range in all subjects expressing the FDH phenotype, and TrT3 levels were above the normal range in only one half. TT4 concentrations correlated positively with TrT3 and TT3. All TT3 values were, however, within the normal range. Free T4 and TSH levels were normal, confirming the euthyroid state in these subjects. FDH was associated with the albumin SacI(+)/Gc 1S haplotype, yielding a LOD (logarithm of the odds ratio) score of 5.53, with a recombination frequency of 0. These data provide strong support that a variant albumin is the cause of FDH in this kindred.
家族性异常白蛋白血症性甲状腺素血症（FDH）是白种人遗传性甲状腺功能正常的甲状腺素血症最常见的病因。它作为常染色体显性性状遗传，总是与高血清总T4（TT4）相关，较少与总T3（TT3）和/或反T3（TrT3）浓度升高相关。通过透析测得的游离T4和促甲状腺激素（TSH）水平正常，提示存在一种T4结合蛋白异常。异常的血清T4载体与白蛋白具有一些物理和免疫学特性，提示它可能就是白蛋白本身。在此，我们在一个瑞士裔的阿米什大家族中，利用白蛋白基因编码序列中的SacI多态性以及与白蛋白基因距离小于1厘摩的群特异性成分（Gc）基因作为标记，显示了FDH与白蛋白基因之间的连锁关系。从该家族的160名成员采集血样，其中22人经等电聚焦分离血清蛋白后T4与血清蛋白结合模式鉴定为FDH。所有表现出FDH表型的受试者血清TT4值均高于正常范围，只有一半受试者的TrT3水平高于正常范围。TT4浓度与TrT3和TT3呈正相关。然而，所有TT3值均在正常范围内。游离T4和TSH水平正常，证实这些受试者甲状腺功能正常。FDH与白蛋白SacI(+)/Gc 1S单倍型相关，获得了5.53的对数优势比（LOD）分数，重组频率为0。这些数据有力支持了一种变异白蛋白是该家族中FDH病因的观点。
