Felbor U, Stöhr H, Amann T, Schönherr U, Apfelstedt-Sylla E, Weber B H
Institut für Humangenetik, Biozentrum, Universität Würzburg, Germany.
J Med Genet. 1996 Mar;33(3):233-6. doi: 10.1136/jmg.33.3.233.
Sorsby's fundus dystrophy (SFD) is a rare autosomal dominant macular disorder with age of onset usually in the fourth decade. It is characterised by loss of central vision owing to subretinal neovascularisation and disciform macular degeneration. In an effort to identify the SFD gene, the disease locus was first mapped to chromosome 22q13-qter by genetic linkage analysis, the same chromosomal region as the gene encoding the tissue inhibitor of metalloproteinases-3 (TIMP3). Subsequently, two separate mutations in TIMP3 were found in affected members of two unrelated SFD pedigrees (Tyr168Cys and Ser181Cys). More recently, two additional SFD related mutations, Ser156Cys and Gly167Cys, have provided further confirmation that heterozygous mutations in TIMP3 are causally responsible for the SFD phenotype. We now report the occurrence of the Tyr168Cys mutation in an SFD patient of Austrian descent and show that this mutation found earlier in an American SFD family arose independently. The new findings add to an emerging pattern of SFD mutations which all seem to affect the C-terminal region of the mature TIMP3 protein. In addition, all known mutations cause a change of an amino acid to a cysteine residue. This suggests a critical role for the additional C-terminal free thiol group in SFD pathogenesis.
索斯比眼底营养不良（SFD）是一种罕见的常染色体显性黄斑疾病，通常在40岁左右发病。其特征是由于视网膜下新生血管形成和盘状黄斑变性导致中心视力丧失。为了确定SFD基因，首先通过遗传连锁分析将疾病基因座定位到22号染色体q13 - qter区域，该区域与编码金属蛋白酶组织抑制剂 - 3（TIMP3）的基因位于同一染色体区域。随后，在两个不相关的SFD家系的患病成员中发现了TIMP3基因的两个不同突变（Tyr168Cys和Ser181Cys）。最近，另外两个与SFD相关的突变Ser156Cys和Gly167Cys进一步证实了TIMP3基因的杂合突变是SFD表型的病因。我们现在报告在一名奥地利裔SFD患者中出现了Tyr168Cys突变，并表明该突变与先前在美国一个SFD家族中发现的突变是独立发生的。这些新发现进一步丰富了SFD突变的模式，所有这些突变似乎都影响成熟TIMP3蛋白的C末端区域。此外，所有已知突变都会导致氨基酸变为半胱氨酸残基。这表明额外的C末端游离巯基在SFD发病机制中起关键作用。
