Dahl N, Hu L J, Chery M, Fardeau M, Gilgenkrantz S, Nivelon-Chevallier A, Sidaner-Noisette I, Mugneret F, Gouyon J B, Gal A
Laboratorire de Génétique Moléculaire des Eucaryotes du CNRS, INSERM U184, Strasbourg, France.
Am J Hum Genet. 1995 May;56(5):1108-15.
A young girl with a clinically moderate form of myotubular myopathy was found to carry a cytogenetically detectable deletion in Xq27-q28. The deletion had occurred de novo on the paternal X chromosome. It encompasses the fragile X (FRAXA) and Hunter syndrome (IDS) loci, and the DXS304 and DXS455 markers, in Xq27.3 and proximal Xq28. Other loci from the proximal half of Xq28 (DXS49, DXS256, DXS258, DXS305, and DXS497) were found intact. As the X-linked myotubular myopathy locus (MTM1) was previously mapped to Xq28 by linkage analysis, the present observation suggested that MTM1 is included in the deletion. However, a significant clinical phenotype is unexpected in a female MTM1 carrier. Analysis of inactive X-specific methylation at the androgen receptor gene showed that the deleted X chromosome was active in approximately 80% of leukocytes. Such unbalanced inactivation may account for the moderate MTM1 phenotype and for the mental retardation that later developed in the patient. This observation is discussed in relation to the hypothesis that a locus modulating X inactivation may lie in the region. Comparison of this deletion with that carried by a male patient with a severe Hunter syndrome phenotype but no myotubular myopathy, in light of recent linkage data on recombinant MTM1 families, led to a considerable refinement of the position of the MTM1 locus, to a region of approximately 600 kb, between DXS304 and DXS497.
一名患有临床中度形式的肌管性肌病的年轻女孩被发现其Xq27 - q28存在细胞遗传学可检测到的缺失。该缺失发生在父本X染色体上，为新发突变。它涵盖了Xq27.3和近端Xq28中的脆性X（FRAXA）和亨特综合征（IDS）基因座以及DXS304和DXS455标记。Xq28近端一半的其他基因座（DXS49、DXS256、DXS258、DXS305和DXS497）未发现缺失。由于X连锁肌管性肌病基因座（MTM1）先前通过连锁分析被定位到Xq28，目前的观察结果表明MTM1包含在该缺失区域内。然而，女性MTM1携带者出现明显临床表型是出乎意料的。对雄激素受体基因的失活X特异性甲基化分析表明，缺失的X染色体在约80%的白细胞中是活跃的。这种不平衡的失活可能解释了中度MTM1表型以及患者后来出现的智力发育迟缓。结合该区域可能存在调节X失活的基因座这一假说对这一观察结果进行了讨论。根据最近关于重组MTM1家系的连锁数据，将该缺失与一名患有严重亨特综合征表型但无肌管性肌病的男性患者的缺失进行比较，使MTM1基因座的定位得到了相当大的细化，定位于DXS304和DXS497之间约600 kb的区域。
