Nakano M, Yamada K, Fain J, Sener E C, Selleck C J, Awad A H, Zwaan J, Mullaney P B, Bosley T M, Engle E C
Genetics, The Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Enders 5, Boston, Massachusetts, USA.
Nat Genet. 2001 Nov;29(3):315-20. doi: 10.1038/ng744.
Isolated strabismus affects 1-5% of the general population. Most forms of strabismus are multifactorial in origin; although there is probably an inherited component, the genetics of these disorders remain unclear. The congenital fibrosis syndromes (CFS) represent a subset of monogenic isolated strabismic disorders that are characterized by restrictive ophthalmoplegia, and include congenital fibrosis of the extraocular muscles (CFEOM) and Duane syndrome (DURS). Neuropathologic studies indicate that these disorders may result from the maldevelopment of the oculomotor (nIII), trochlear (nIV) and abducens (nVI) cranial nerve nuclei. To date, five CFS loci have been mapped (FEOM1, FEOM2, FEOM3, DURS1 and DURS2), but no genes have been identified. Here, we report three mutations in ARIX (also known as PHOX2A) in four CFEOM2 pedigrees. ARIX encodes a homeodomain transcription factor protein previously shown to be required for nIII/nIV development in mouse and zebrafish. Two of the mutations are predicted to disrupt splicing, whereas the third alters an amino acid within the conserved brachyury-like domain. These findings confirm the hypothesis that CFEOM2 results from the abnormal development of nIII/nIV (ref. 7) and emphasize a critical role for ARIX in the development of these midbrain motor nuclei.
孤立性斜视影响1%至5%的普通人群。大多数斜视形式的病因是多因素的；尽管可能存在遗传因素，但这些疾病的遗传学仍不清楚。先天性纤维化综合征（CFS）是单基因孤立性斜视疾病的一个子集，其特征为限制性眼肌麻痹，包括眼外肌先天性纤维化（CFEOM）和杜安综合征（DURS）。神经病理学研究表明，这些疾病可能是由于动眼神经（nIII）、滑车神经（nIV）和展神经（nVI）颅神经核发育异常所致。迄今为止，已定位了五个CFS基因座（FEOM1、FEOM2、FEOM3、DURS1和DURS2），但尚未鉴定出相关基因。在此，我们报告了四个CFEOM2家系中ARIX（也称为PHOX2A）的三个突变。ARIX编码一种同源结构域转录因子蛋白，先前已证明该蛋白在小鼠和斑马鱼的nIII/nIV发育中是必需的。其中两个突变预计会破坏剪接，而第三个突变会改变保守的短尾样结构域内的一个氨基酸。这些发现证实了CFEOM2是由nIII/nIV发育异常导致的这一假设（参考文献7），并强调了ARIX在这些中脑运动核发育中的关键作用。
