Daiger Stephen P, Sullivan Lori S, Bowne Sara J, Koboldt Daniel C, Blanton Susan H, Wheaton Dianna K, Avery Cheryl E, Cadena Elizabeth D, Koenekoop Robert K, Fulton Robert S, Wilson Richard K, Weinstock George M, Lewis Richard A, Birch David G
Human Genetics Center, School of Public Health, The University of Texas HSC, 1200 Pressler St., Houston, TX, 77030, USA.
Ruiz Department of Ophthalmology and Visual Science, Medical School, The University of Texas Health Science Center, Houston, TX, 77030, USA.
Adv Exp Med Biol. 2016;854:193-200. doi: 10.1007/978-3-319-17121-0_26.
Whole-genome linkage mapping identified a region on chromosome 10q21.3-q22.1 with a maximum LOD score of 3.0 at 0 % recombination in a six-generation family with autosomal dominant retinitis pigmentosa (adRP). All known adRP genes and X-linked RP genes were excluded in the family by a combination of methods. Whole-exome next-generation sequencing revealed a missense mutation in hexokinase 1, HK1 c.2539G > A, p.Glu847Lys, tracking with disease in all affected family members. One severely-affected male is homozygous for this region by linkage analysis and has two copies of the mutation. No other potential mutations were detected in the linkage region nor were any candidates identified elsewhere in the genome. Subsequent testing detected the same mutation in four additional, unrelated adRP families, for a total of five mutations in 404 probands tested (1.2 %). Of the five families, three are from the Acadian population in Louisiana, one is French Canadian and one is Sicilian. Haplotype analysis of the affected chromosome in each family and the homozygous individual revealed a rare, shared haplotype of 450 kb, suggesting an ancient founder mutation. HK1 is a widely-expressed gene, with multiple, abundant retinal transcripts, coding for hexokinase 1. Hexokinase catalyzes phosphorylation of glucose to glusose-6-phospate, the first step in glycolysis. The Glu847Lys mutation is in a highly-conserved site, outside of the active site or known functional sites.
全基因组连锁图谱分析在一个患常染色体显性视网膜色素变性（adRP）的六代家系中，确定了10号染色体q21.3 - q22.1区域，在0%重组率时最大对数优势（LOD）得分为3.0。通过多种方法组合，该家系中所有已知的adRP基因和X连锁RP基因均被排除。全外显子组二代测序揭示了己糖激酶1（HK1）存在一个错义突变，即HK1 c.2539G＞A，p.Glu847Lys，在所有患病家庭成员中该突变与疾病共分离。一名严重受累男性通过连锁分析在该区域为纯合子，有两份该突变拷贝。在连锁区域未检测到其他潜在突变，在基因组其他位置也未鉴定出任何候选基因。随后的检测在另外四个不相关的adRP家系中也检测到相同突变，在总共检测的404名先证者中有5个突变（1.2%）。这五个家系中，三个来自路易斯安那州的阿卡迪亚人群，一个是法裔加拿大人，一个是西西里人。对每个家系中受累染色体以及该纯合个体进行单倍型分析，发现了一个450 kb的罕见共享单倍型，提示存在一个古老的奠基者突变。HK1是一个广泛表达的基因，有多个丰富的视网膜转录本，编码己糖激酶1。己糖激酶催化葡萄糖磷酸化生成葡萄糖 - 6 - 磷酸，这是糖酵解的第一步。Glu847Lys突变位于一个高度保守的位点，在活性位点或已知功能位点之外。
