HUMAN BIOCHEMICAL GENETICS

该科成员已将胱氨酸病基因与标记D17 S1584联系起来 在17号染色体短臂上，最大lod值为10.89， θ = 0.03。 他们已经构建了一个YAC重叠群， 他们试图分离胱氨酸病基因本身。 门克斯病基因中的几个突变已经被确定， 这种X连锁疾病的患者，基因型与 在两个家庭中对早期组氨酸铜治疗有反应。 在一个例子中，一个外显子剪接供体位点上的G到T颠换引起了一个突变。 在密码子724处谷氨酰胺到组氨酸的取代，跳过一个， 两个或三个外显子，和过早终止。 两个相关的孩子 在生命早期用组氨酸铜治疗， 两者都没有正常的神经发育结果，这表明 Q724 H突变不能保留足够的残留Menkes ATP酶 活性，从铜中获得显著临床益处 更换. 相比之下，不同的家族表现出5碱基 在226 bp外显子上游的剪接受体位点复制， 门克斯编码序列的中间，有一个转录本， 含有前面77 bp外显子的缺失。 这创造了一个开放的 阅读框和RNA酶保护研究显示， Menkes基因转录本。 这个家庭中有一个受影响的男孩， 铜从8天大，现在有正常的神经发育在14个月 年龄。 猪血清糖蛋白中N-连接寡糖的分析 患有碳水化合物缺乏糖蛋白综合征的患者显示 疾病的生化基础存在异质性，一些患者 证明了长胆醇形成早期的缺陷 低聚糖。 酪氨酸转运系统的特征在于黑素体中的 小鼠黑素细胞，并发现在粉眼稀释液中有功能 突变体，眼皮肤白化病II型的小鼠同源物。 Dolichol已被鉴定为蜡样脂褐素的成分 它储存在病人的细胞溶酶体中 Hermansky-Pudlak综合征，一种伴有血小板储存的白化病 池缺陷。

Members of the Section have linked the cystinosis gene to marker D17S1584 on the short arm of chromosome 17 with a maximum lod score of 10.89 at theta = 0.03. They have constructed a YAC contig spanning the region of interest in an attempt to isolate the cystinosis gene itself. Several mutations in the Menkes disease gene have been identified in patients with this X-linked disorder, and genotypes have been correlated with responsiveness to early copper histidine therapy in two families. In one, a G to T transversion at a -1 exonic splice donor site caused a glutamine to histidine substitution at codon 724, with skipping of one, two, or three exons, and premature termination. Two related children with this mutation were treated early in life with copper histidine, and neither had a normal neurodevelopmental outcome, suggesting that the Q724H mutation did not preserve sufficient residual Menkes ATPase activity for significant clinical benefit to accrue from copper replacement. In contrast, a different family exhibited a 5-base duplication at a splice acceptor site just upstream of a 226 bp exon in the middle of the Menkes coding sequence, with one transcript which contained a deletion of the preceeding 77 bp exon. This created an open reading frame, and RNAse protection studies revealed 25% of the normal Menkes gene transcript. One affected boy in this family, treated with copper from 8 days of age, now has normal neurodevelopment at 14 months of age. Analysis of N-linked oligosaccharides on serum glycoproteins from patients with Carbohydrate Deficient Glycoprotein Syndrome revealed heterogeneity in the biochemical basis of the disease, with some patients demonstrating a defect early in the formation of dolichol- oligosaccharides. A tyrosine transport system has been characterized in the melanosomes of murine melanocytes and found to be functional in the pink-eyed dilution mutant, the murine homologue of oculocutaneous albinism type II. Dolichols have been identified as components of the ceroid lipofuscin which is stored in the cellular lysosomes of patients with Hermansky-Pudlak syndrome, a type of albinism with a platelet storage pool defect.