Kato Mitsuhiro, Das Soma, Petras Kristin, Kitamura Kunio, Morohashi Ken-Ichirou, Abuelo Diane N, Barr Mason, Bonneau Dominique, Brady Angela F, Carpenter Nancy J, Cipero Karen L, Frisone Francesco, Fukuda Takayuki, Guerrini Renzo, Iida Eri, Itoh Masayuki, Lewanda Amy Feldman, Nanba Yukiko, Oka Akira, Proud Virginia K, Saugier-Veber Pascale, Schelley Susan L, Selicorni Angelo, Shaner Rachel, Silengo Margherita, Stewart Fiona, Sugiyama Noriyuki, Toyama Jun, Toutain Annick, Vargas Ana Lía, Yanazawa Masako, Zackai Elaine H, Dobyns William B
Department of Human Genetics, The University of Chicago, Chicago, Illinois.
Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan.
Hum Mutat. 2004 Feb;23(2):147-159. doi: 10.1002/humu.10310.
We recently identified mutations of ARX in nine genotypic males with X-linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia. We obtained detailed clinical information on all 29 affected males, including the nine previously reported subjects. Premature termination mutations consisting of large deletions, frameshifts, nonsense mutations, and splice site mutations in exons 1 to 4 caused XLAG or hydranencephaly with abnormal genitalia. Nonconservative missense mutations within the homeobox caused less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome. A nonconservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. In addition, several less severe phenotypes without malformations have been reported, including mental retardation with cryptogenic infantile spasms (West syndrome), other seizure types, dystonia or autism, and nonsyndromic mental retardation. The ARX mutations associated with these phenotypes have included polyalanine expansions or duplications, missense mutations, and one deletion of exon 5. Together, the group of phenotypes associated with ARX mutations demonstrates remarkable pleiotropy, but also comprises a nearly continuous series of developmental disorders that begins with hydranencephaly, lissencephaly, and agenesis of the corpus callosum, and ends with a series of overlapping syndromes with apparently normal brain structure.
我们最近在9名患有伴有生殖器异常的X连锁无脑回畸形（XLAG）的基因型男性以及几名患有孤立性胼胝体发育不全（ACC）的女性亲属中发现了ARX基因突变。我们现在报告来自16个家庭的20名基因型男性中13个新的和2个复发的ARX突变，以及1个意义不确定的核苷酸变化。大多数患者患有XLAG，但有2名患有积水性无脑畸形和生殖器异常，来自一个家庭的3名男性患有Proud综合征或伴有生殖器异常的ACC。我们获得了所有29名受影响男性的详细临床信息，包括9名先前报告的受试者。外显子1至4中由大的缺失、移码、无义突变和剪接位点突变组成的过早终止突变导致XLAG或伴有生殖器异常的积水性无脑畸形。同源异型框内的非保守错义突变导致不太严重的XLAG，而同源异型域内的保守替换导致Proud综合征。靠近C端无触角结构域的非保守错义突变导致伴有小头畸形和轻度小脑发育不全的异常严重的XLAG。此外，还报告了几种没有畸形的不太严重的表型，包括伴有隐源性婴儿痉挛（韦斯特综合征）的智力迟钝、其他癫痫类型、肌张力障碍或自闭症以及非综合征性智力迟钝。与这些表型相关的ARX突变包括多聚丙氨酸扩展或重复、错义突变以及外显子5的一个缺失。总之，与ARX突变相关的一组表型表现出显著的多效性，但也包括一系列几乎连续的发育障碍，从积水性无脑畸形、无脑回畸形和胼胝体发育不全开始，到一系列具有明显正常脑结构的重叠综合征结束。
