Godfrey Caroline, Clement Emma, Mein Rachael, Brockington Martin, Smith Janine, Talim Beril, Straub Volker, Robb Stephanie, Quinlivan Ros, Feng Lucy, Jimenez-Mallebrera Cecilia, Mercuri Eugenio, Manzur Adnan Y, Kinali Maria, Torelli Silvia, Brown Susan C, Sewry Caroline A, Bushby Kate, Topaloglu Haluk, North Kathryn, Abbs Stephen, Muntoni Francesco
Dubowitz Neuromuscular Unit, Hammersmith Hospital, Imperial College, London, UK.
Brain. 2007 Oct;130(Pt 10):2725-35. doi: 10.1093/brain/awm212. Epub 2007 Sep 18.
Muscular dystrophies with reduced glycosylation of alpha-dystroglycan (alpha-DG), commonly referred to as dystroglycanopathies, are a heterogeneous group of autosomal recessive conditions which include a wide spectrum of clinical severity. Reported phenotypes range from severe congenital onset Walker-Warburg syndrome (WWS) with severe structural brain and eye involvement, to relatively mild adult onset limb girdle muscular dystrophy (LGMD). Specific clinical syndromes were originally described in association with mutations in any one of six demonstrated or putative glycosyltransferases. Work performed on patients with mutations in the FKRP gene has identified that the spectrum of phenotypes due to mutations in this gene is much wider than originally assumed. To further define the mutation frequency and phenotypes associated with mutations in the other five genes, we studied a large cohort of patients with evidence of a dystroglycanopathy. Exclusion of mutations in FKRP was a prerequisite for participation in this study. Ninety-two probands were screened for mutations in POMT1, POMT2, POMGnT1, fukutin and LARGE. Homozygous and compound heterozygous mutations were detected in a total of 31 probands (34 individuals from 31 families); 37 different mutations were identified, of which 32 were novel. Mutations in POMT2 were the most prevalent in our cohort with nine cases, followed by POMT1 with eight cases, POMGnT1 with seven cases, fukutin with six cases and LARGE with only a single case. All patients with POMT1 and POMT2 mutations had evidence of either structural or functional central nervous system involvement including four patients with mental retardation and a LGMD phenotype. In contrast mutations in fukutin and POMGnT1 were detected in four patients with LGMD and no evidence of brain involvement. The majority of patients (six out of nine) with mutations in POMT2 had a Muscle-Eye-Brain (MEB)-like condition. In addition we identified a mutation in the gene LARGE in a patient with WWS. Our data expands the clinical phenotypes associated with POMT1, POMT2, POMGnT1, fukutin and LARGE mutations. Mutations in these five glycosyltransferase genes were detected in 34% of patients indicating that, after the exclusion of FKRP, the majority of patients with a dystroglycanopathy harbour mutations in novel genes.
α-肌营养不良聚糖（α-DG）糖基化减少的肌营养不良症，通常称为糖基化肌营养不良症，是一组常染色体隐性疾病的异质性群体，临床严重程度范围广泛。报道的表型从严重的先天性沃克 - 沃尔伯格综合征（WWS）伴严重的脑和眼结构受累，到相对轻度的成人起病肢带型肌营养不良症（LGMD）。最初描述的特定临床综合征与六种已证实或推定的糖基转移酶中任何一种的突变有关。对FKRP基因突变患者的研究发现，该基因突变导致的表型谱比最初设想的要广泛得多。为了进一步确定与其他五个基因突变相关的突变频率和表型，我们研究了一大群有糖基化肌营养不良症证据的患者。排除FKRP基因突变是参与本研究的先决条件。对92名先证者进行了POMT1、POMT2、POMGnT1、福库亭和LARGE基因突变的筛查。总共在31名先证者（来自31个家庭的34名个体）中检测到纯合和复合杂合突变；鉴定出37种不同的突变，其中32种是新的。POMT2基因突变在我们的队列中最常见，有9例，其次是POMT1基因有8例，POMGnT1基因有7例，福库亭基因有6例，LARGE基因只有1例。所有POMT1和POMT2基因突变的患者都有中枢神经系统结构或功能受累的证据，包括4例智力发育迟缓且有LGMD表型的患者。相比之下，在4例LGMD患者中检测到福库亭和POMGnT1基因突变，且无脑受累证据。大多数（9例中的6例）POMT2基因突变患者有类似肌肉 - 眼 - 脑（MEB）的病症。此外，我们在一名WWS患者中鉴定出LARGE基因突变。我们的数据扩展了与POMT1、POMT2、POMGnT1、福库亭和LARGE基因突变相关的临床表型。在34%的患者中检测到这五个糖基转移酶基因突变，这表明在排除FKRP基因后，大多数糖基化肌营养不良症患者携带新基因的突变。
