Aarskog综合征样家系的新致病基因筛查
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摘要
Aarskog综合征(Aarskog Syndrome, AAS)是一种罕见的遗传性面-指-生殖器异常综合征,由Aarskog在1970年首先报道。AAS主要表现为身材矮小、面部、指(趾)和生殖器形态改变,但程度各异,还可合并其他多种异常,目前诊断必备的表型尚不明确。AAS是一种由位于Xp11.21的FGD1基因突变所致的X连锁隐性遗传性疾病。FGD1突变的致病机制与细胞骨架有关,它编码的一种鸟嘌呤核苷酸转化因子(guanine nucleotide exchange factor,GEF),可特异性地激活一种小G蛋白酶—RhoGTP酶Cdc42。此外,AAS也可呈现为常染色体显性遗传、常染色体隐性遗传、以及与FGD1基因无关的X连锁显性遗传,甚至在同一个AAS家系中呈现两种不同的遗传模式。然而jGD1之外的AAS新致病基因尚未找到。
本研究报道了国内第一个AAS家系,含有两对亲近结婚,9位可疑患者。患病者具有AAS的典型特征,如身材矮小、面部器官距离过宽、披肩样阴囊和第五小指弯曲等,但无近端指间关节外展。还有一些在AAS中并不常见的症状如菱形发际、牙齿异常、通贯手、拇指外展、颈椎融合、桶装胸、球状拇趾、包茎、隐睾和智力低下等。本家系的患者还出现了一些新的异常,如中枢性面瘫、听力下降、张口困难、先天性第12肋缺失和不明原因的尿频等。从先证者父系的发病情况分析,为男-男遗传,不支持X连锁遗传。同时患者间表型差异明显,第Ⅲ代患者表型较轻,第Ⅳ代患者的父母各为近亲结婚,表型较重,可能合并有不同于第Ⅲ代患者的遗传基础。
本家系内所有患者FGDl基因的启动子和外显子区域的序列未见异常突变,基因连锁分析排除了FGDl基因在测序区域之外可能致病的突变。同时CNV检测排除了Xp11.21(FGD1基因所在位置)等目前已知CNV变异的422种遗传性疾病。因此考虑FGD1不是本家系的致病基因。进一步通过全外显子组捕获和二代测序,也没有找到家系中所有患病个体共有的致病基因。但根据症状分层筛查,发现了症状最重的先证者中RAB35基因的一个新突变,符合常染色体隐性遗传模式。RAB35基因编码蛋白的保守性结构域中的第155位氨基酸缬氨酸在多物种间高度保守,先证者中的突变导致这个氨基酸变成了异亮氨酸。RAB35与Cdc42都是小G蛋白酶,突变氨基酸位于RAB35与其特异性底物GEF结合的复合体中,蛋白三维结构预测提示突变后RAB35的构象发生重要改变。目前已有研究表明,RAB35是细胞骨架的调控蛋白,并与Cdc42的活性有关,参与骨骼、毛发、神经系统等可能与AAS有关的病理生理过程。因此,RAB35(?)可能是AAS的一个新致病基因。
综上,该Aarskog综合征样家系的研究表明,AAS患者可能有多个突变基因,从而导致个体间表型的多样性。进一步研究(?)AB35等可能致病基因的功能、筛查其他的AAS新致病基因,并研究基因间是否有相互作用,将有助于明确AAS的特异性表型,以建立明确的诊断标准和干预方向。
Aarskog syndrome or Aarskog-Scott syndrome (AAS) was referred to by Aarskog as Faciodigitogenital syndrome in1970, and is characterized by short stature, and facial, limb, and genital anomalies. Clinical features of AAS show remarkable inter-familial and intra-familial variability, and it is uncertain which phenotype is necessary for diagnosis. AAS can be inherited as an X-linked disorder caused by FGD1mutations at Xp11.21. FGD1encodes a guimine nucleotide exchange factor (GEF) that can specifically activate Cdc42, a RhoGTPase that controls the organization of the actin cytoskeleton. However, there is also evidence that AAS can be inherited in an autosomal dominant mode, an autosomal recessive mode or an X-linked dominant pattern. Different inheritant modes might occur even in one pedigree. However, the potential causative gene other than FGD1has been not reported as yet.
Here we report on a Chinese family in whom9members show signs of AAS. Affected members had manifestations characteristic for AAS such as short stature, hypertelorism, shawl scrotum, the fifth finger clinodactyly, broad hands with interdigital webbing and hyperextensible elbows, but no hyperextension of the proximal interphalangeal joints. They did have several other features less common but still found in AAS such as widow's peak, highly arched palate, abnormal teeth, retarded bone age, four-finger flexion creases, adducted thumbs, vertebral malformations, pectus excavatum, broad feet with bulbous toes, phimosis, cryptorchidism and mental retardation. Furthermore, the present family showed additional characteristics such as central facial paralysis, trismus, decreased hearing, congenital absent12th ribs and frequent micturition. Male to male inheritance in the pedigree suggested an autosomal dominant or recessive pattern of inheritance. The affected individuals in generation IV came from the two families of consanguineous marriage, and they might carry additional mutation as their clinical phenotypes were obviously more severe than those from generation III.
The sequencing of the18exons and promoter of FGD1showed no pathogenic mutation. The linkage analysis also excluded FGD1as the candidate gene. A submicroscopic chromosome imbalance is less likely at Xp11.21(FGD1) and other421positions identified for common known disorders. Whole-exome sequencing was then carried out to screen the novel pathogenic genes, and no compelling candidate gene containing novel variants in all affected individuals were found. When grouping the affected individuals according to their phenotype variation, RAB35was identified as a compelling pathogenic gene, which carried a homozygous missense mutation (chrl2: g.119021012>T, c.463G>A, p.V155I) in the most severely affected proband. His consanguineously mated parents both carried heterogenous mutation, and it presented a recessive mode of inheritance. The155th amino acid is the conserved domain, and phylogenetically conservative in various species such as nematode and10vertebrates including danio rerio. RAB35is also a small GTPase, and the complex with its GEF includes residues4-33and35-177of RAB35. Protein modeling implied a significant conformational change of the mutant RAB35. RAB35is a regulator of actin cytoskeleton, which is associated with the activation of Cdc42. RAB35is also implicated in several crucial pathophysiological processes that might related to AAS, such as bone metabolism, hair development and the function of nervous system.
In summary, AAS might be caused by more than one gene, and the mutation in RAB35may underlie a disorder resembling AAS. Further work is required to fully understand the underlying mechanisms of the RAB35mutation induced alterations. The phenotypic diversity of AAS might be, at least partially, due to the presence of the mutation(s) in other pathogenic genes than FGD1. It is could not be completely excluded that novel causative genes might coexist even in those with FGD1mutation. The investigation of these potential causative genes and their interactions, might contribute to knowing the specific phenotype for AAS, and to establishing more specific diagnostic criteria and intervention.
本研究报道了国内第一个AAS家系,含有两对亲近结婚,9位可疑患者。患病者具有AAS的典型特征,如身材矮小、面部器官距离过宽、披肩样阴囊和第五小指弯曲等,但无近端指间关节外展。还有一些在AAS中并不常见的症状如菱形发际、牙齿异常、通贯手、拇指外展、颈椎融合、桶装胸、球状拇趾、包茎、隐睾和智力低下等。本家系的患者还出现了一些新的异常,如中枢性面瘫、听力下降、张口困难、先天性第12肋缺失和不明原因的尿频等。从先证者父系的发病情况分析,为男-男遗传,不支持X连锁遗传。同时患者间表型差异明显,第Ⅲ代患者表型较轻,第Ⅳ代患者的父母各为近亲结婚,表型较重,可能合并有不同于第Ⅲ代患者的遗传基础。
本家系内所有患者FGDl基因的启动子和外显子区域的序列未见异常突变,基因连锁分析排除了FGDl基因在测序区域之外可能致病的突变。同时CNV检测排除了Xp11.21(FGD1基因所在位置)等目前已知CNV变异的422种遗传性疾病。因此考虑FGD1不是本家系的致病基因。进一步通过全外显子组捕获和二代测序,也没有找到家系中所有患病个体共有的致病基因。但根据症状分层筛查,发现了症状最重的先证者中RAB35基因的一个新突变,符合常染色体隐性遗传模式。RAB35基因编码蛋白的保守性结构域中的第155位氨基酸缬氨酸在多物种间高度保守,先证者中的突变导致这个氨基酸变成了异亮氨酸。RAB35与Cdc42都是小G蛋白酶,突变氨基酸位于RAB35与其特异性底物GEF结合的复合体中,蛋白三维结构预测提示突变后RAB35的构象发生重要改变。目前已有研究表明,RAB35是细胞骨架的调控蛋白,并与Cdc42的活性有关,参与骨骼、毛发、神经系统等可能与AAS有关的病理生理过程。因此,RAB35(?)可能是AAS的一个新致病基因。
综上,该Aarskog综合征样家系的研究表明,AAS患者可能有多个突变基因,从而导致个体间表型的多样性。进一步研究(?)AB35等可能致病基因的功能、筛查其他的AAS新致病基因,并研究基因间是否有相互作用,将有助于明确AAS的特异性表型,以建立明确的诊断标准和干预方向。
Aarskog syndrome or Aarskog-Scott syndrome (AAS) was referred to by Aarskog as Faciodigitogenital syndrome in1970, and is characterized by short stature, and facial, limb, and genital anomalies. Clinical features of AAS show remarkable inter-familial and intra-familial variability, and it is uncertain which phenotype is necessary for diagnosis. AAS can be inherited as an X-linked disorder caused by FGD1mutations at Xp11.21. FGD1encodes a guimine nucleotide exchange factor (GEF) that can specifically activate Cdc42, a RhoGTPase that controls the organization of the actin cytoskeleton. However, there is also evidence that AAS can be inherited in an autosomal dominant mode, an autosomal recessive mode or an X-linked dominant pattern. Different inheritant modes might occur even in one pedigree. However, the potential causative gene other than FGD1has been not reported as yet.
Here we report on a Chinese family in whom9members show signs of AAS. Affected members had manifestations characteristic for AAS such as short stature, hypertelorism, shawl scrotum, the fifth finger clinodactyly, broad hands with interdigital webbing and hyperextensible elbows, but no hyperextension of the proximal interphalangeal joints. They did have several other features less common but still found in AAS such as widow's peak, highly arched palate, abnormal teeth, retarded bone age, four-finger flexion creases, adducted thumbs, vertebral malformations, pectus excavatum, broad feet with bulbous toes, phimosis, cryptorchidism and mental retardation. Furthermore, the present family showed additional characteristics such as central facial paralysis, trismus, decreased hearing, congenital absent12th ribs and frequent micturition. Male to male inheritance in the pedigree suggested an autosomal dominant or recessive pattern of inheritance. The affected individuals in generation IV came from the two families of consanguineous marriage, and they might carry additional mutation as their clinical phenotypes were obviously more severe than those from generation III.
The sequencing of the18exons and promoter of FGD1showed no pathogenic mutation. The linkage analysis also excluded FGD1as the candidate gene. A submicroscopic chromosome imbalance is less likely at Xp11.21(FGD1) and other421positions identified for common known disorders. Whole-exome sequencing was then carried out to screen the novel pathogenic genes, and no compelling candidate gene containing novel variants in all affected individuals were found. When grouping the affected individuals according to their phenotype variation, RAB35was identified as a compelling pathogenic gene, which carried a homozygous missense mutation (chrl2: g.119021012>T, c.463G>A, p.V155I) in the most severely affected proband. His consanguineously mated parents both carried heterogenous mutation, and it presented a recessive mode of inheritance. The155th amino acid is the conserved domain, and phylogenetically conservative in various species such as nematode and10vertebrates including danio rerio. RAB35is also a small GTPase, and the complex with its GEF includes residues4-33and35-177of RAB35. Protein modeling implied a significant conformational change of the mutant RAB35. RAB35is a regulator of actin cytoskeleton, which is associated with the activation of Cdc42. RAB35is also implicated in several crucial pathophysiological processes that might related to AAS, such as bone metabolism, hair development and the function of nervous system.
In summary, AAS might be caused by more than one gene, and the mutation in RAB35may underlie a disorder resembling AAS. Further work is required to fully understand the underlying mechanisms of the RAB35mutation induced alterations. The phenotypic diversity of AAS might be, at least partially, due to the presence of the mutation(s) in other pathogenic genes than FGD1. It is could not be completely excluded that novel causative genes might coexist even in those with FGD1mutation. The investigation of these potential causative genes and their interactions, might contribute to knowing the specific phenotype for AAS, and to establishing more specific diagnostic criteria and intervention.
引文
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