Prager Sebastian, Wollmann Hartmut A, Mergenthaler Susanne, Mavany Miriam, Eggermann Katja, Ranke Michael B, Eggermann Thomas
Institute of Human Genetics, RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany.
Genet Test. 2003 Fall;7(3):259-63. doi: 10.1089/109065703322537304.
Silver-Russell syndrome (SRS) is a syndrome of severe pre- and postnatal growth retardation and typical dysmorphic features. Rare chromosomal aberrations have been reported in SRS; among these are two balanced translocations involving 17q24-q25. Recently, we described a patient with a paternally inherited heterozygous deletion of the chorionic somatomammotropin hormone 1 (CSH1) gene. The CSH1 gene is member of the growth hormone (GH) gene cluster on 17q, which consists of two growth hormone genes and three CSH genes. Genomic alterations in the GH cluster are well known, causing different phenotypes depending on the size of the deletion and the genes involved. By screening 63 SRS cases with marker D17S254, we have detected 2 further patients with a heterozygous deletion in the GH cluster. Quantitative analysis using restriction assays confirmed these findings. Additionally, in a cohort of 17 patients with isolated intrauterine and postnatal growth retardation, we detected a further patient to be carrier of a CSH1 deletion. Screening of 141 unrelated controls revealed hemizygosity in one person for which data on growth were not available. We additionally analyzed our cohort of SRS patients for mutations in CSH1 and its 3' neighbour GH2. However, analyses failed to reveal any pathogenic mutation. While the central role of GH1 in human growth is well established, the physiological roles of CSH1 and other components of the cluster are unclear. The increased prevalence of hemizygosity of CSH1 in our population in comparison to controls indicates a role for CSH1 haploinsufficiency in the etiology of growth retardation. Investigation of CSH1 deletions in further SRS and growth retarded patients will enable us to establish under which circumstances haploinsufficiency of CSH1 is likely to result in clinical changes.
Silver-Russell综合征（SRS）是一种严重的产前和产后生长发育迟缓并伴有典型畸形特征的综合征。已有报道SRS存在罕见的染色体畸变；其中包括涉及17q24-q25的两个平衡易位。最近，我们描述了一名患有父系遗传的绒毛膜生长催乳素激素1（CSH1）基因杂合缺失的患者。CSH1基因是位于17q的生长激素（GH）基因簇的成员，该基因簇由两个生长激素基因和三个CSH基因组成。GH基因簇中的基因组改变是众所周知的，根据缺失的大小和涉及的基因会导致不同的表型。通过用标记D17S254筛查63例SRS病例，我们又检测到另外2例GH基因簇杂合缺失的患者。使用限制性分析的定量分析证实了这些发现。此外，在一组17例单纯宫内和产后生长发育迟缓的患者中，我们又检测到1例CSH1缺失携带者。对141名无关对照的筛查发现1人存在半合子状态，但没有其生长数据。我们还分析了我们的SRS患者队列中CSH1及其3'邻接基因GH2的突变情况。然而，分析未发现任何致病突变。虽然GH1在人类生长中的核心作用已得到充分确立，但CSH1和该基因簇其他成分的生理作用尚不清楚。与对照组相比，我们人群中CSH1半合子状态的患病率增加表明CSH1单倍体不足在生长发育迟缓病因中起作用。对更多SRS和生长发育迟缓患者的CSH1缺失进行研究，将使我们能够确定在何种情况下CSH1单倍体不足可能导致临床变化。
