Drage Berentsen Ragnhild, Haukanes Bjørn I, Júlíusson Pétur B, Rosendahl Karen, Houge Gunnar
Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
Mol Syndromol. 2019 Jan;9(5):228-234. doi: 10.1159/000492418. Epub 2018 Aug 15.
A 4-generation family with multiple synostoses syndrome type 4 (SYNS4) is reported, the third family identified so far. The phenotype segregated with a previously undescribed Asn399Lys (c.1197C>A) substitution in . N399 is part of a hydrophobic pocket critical for binding the BMP/GDF antagonist noggin. The N399K substitution renders GDF6 more similar to noggin-resistant members of the BMP family, namely GDF2 and BMP10, both of which contain lysine in the corresponding position. To further define the SYNS4 phenotype, we examined 6 of 9 affected family members. The phenotype was carpal and tarsal synostoses with painful feet after walking, but the condition could also be asymptomatic. Interestingly, unlike the previous SYNS4 families, the family presented here has no history of hearing loss, and a 73-year-old mutation carrier had normal audiometry for his age. Based on structure modelling, BMPR2 binding should not be affected by the GDF6-N399K substitution, unlike the S429R and Y444N mutations found in the 2 other families. Hypothetically, this difference may be related to lack of hearing loss.
本文报道了一个患有4型多发性关节强直综合征（SYNS4）的四代家族，这是迄今为止发现的第三个此类家族。该表型与 中一个先前未描述的Asn399Lys（c.1197C>A）替换相关。N399是与骨形态发生蛋白/生长分化因子（BMP/GDF）拮抗剂头蛋白结合至关重要的疏水口袋的一部分。N399K替换使GDF6更类似于BMP家族中对头蛋白有抗性的成员，即GDF2和BMP10，这两者在相应位置都含有赖氨酸。为了进一步明确SYNS4表型，我们检查了9名受影响家族成员中的6名。表型为腕骨和跗骨融合，行走后足部疼痛，但也可能无症状。有趣的是，与之前的SYNS4家族不同，这里呈现的家族没有听力损失病史，一名73岁的突变携带者听力测试结果与其年龄相符。基于结构建模，与在其他两个家族中发现的S429R和Y444N突变不同，BMPR2结合不应受GDF6 - N399K替换的影响。据推测，这种差异可能与听力损失的缺失有关。
