A novel missense variant (Gln220Arg) of GNB4 encoding guanine nucleotide-binding protein,subunit beta-4 in a Japanese family with autosomal dominant motor and sensory neuropathy

Dominant intermediate Charcot–Marie–Tooth disease F (CMTDIF) is an autosomal dominant hereditary form of Charcot–Marie–Tooth disease (CMT) caused by variations in the guanine nucleotide-binding protein, subunit beta-4 gene (GNB4). We examined two Japanese familial cases with CMT. Case 1 was a 49-year-old male whose chief complaint was slowly progressive gait disturbance and limb dysesthesia that appeared at the age of 47. On neurological examination, he showed hyporeflexia or areflexia, distal limb muscle weakness, and distal sensory impairment with lower dominancy. Nerve conduction studies demonstrated demyelinating sensorimotor neuropathy with reduced action potentials in the lower limbs. Case 2 was an 80-year-old man, Case 1's father, who reported difficulty in riding a bicycle at the age of 76. On neurological examination, he showed areflexia in the upper and lower limbs. Distal sensory impairment in the lower limbs was also observed. Nerve conduction studies revealed mainly axonal involvement. Exome sequencing identified a novel heterozygous nonsynonymous variant (NM_021629.3:c.659T > C [p.Gln220Arg]) in GNB4 exon 8, which is known to be responsible for CMT. Sanger sequencing confirmed that both patients are heterozygous for the variation, which causes an amino acid substitution, Gln220Arg, in the highly conserved region of the WD40 domain of GNB4. The frequency of this variant in the Exome Aggregation Consortium Database was 0.000008247, and we confirmed its absence in 502 Japanese control subjects. We conclude that this novel GNB4 variant is causative for CMTDIF in these patients, who represent the first record of the disease in the Japanese population.     

1例腓骨肌萎缩症亚急性进展误诊分析

1病例介绍 患者,男性,51岁。主因四肢无力伴麻木进行性加重1年转入我院。患者于人院前1年开始出现四肢无力伴麻木,以双下肢为著,呈进行性加重,经常摔倒,需要轮椅帮助日常活动。当地医院以慢性炎性脱髓鞘性周围神经病（CIDP）收入院。当地医院给予静脉滴注免疫球蛋白,类固醇和血浆置换治疗后无效,为进一步诊治转人我院。     

Cdc42 regulates schwann cell radial sorting and myelin sheath folding through NF2/merlin‐dependent and independent signaling

The Rho family GTPase Cdc42 has been implicated in developmental Schwann cell (SC) proliferation, providing sufficient SCs for radial sorting of axons preceding SC differentiation in the peripheral nervous system. We generated Cdc42 conditional knockout (Cdc42‐CKO) mice and confirmed aberrant axon sorting in Cdc42‐CKO nerves. In adult Cdc42‐CKO nerves, blood vessels were enlarged, and mature Remak bundles containing small axons were absent. Abnormal infoldings and outfoldings of myelin sheaths developed in Cdc42‐CKO nerves, mimicking pathological features of Charcot‐Marie‐Tooth (CMT) disease. The NF2/merlin tumor suppressor has been implicated up‐ and down‐stream of Cdc42. In Cdc42‐CKO;NF2‐del double mutant mice, radial sorting defects seen in Cdc42‐CKO nerves were rescued, while changes in myelin sheaths in Cdc42‐CKO nerves were not. Phosphorylation of Focal adhesion kinase (FAK) and P‐GSK3β, as well as expression of β‐catenin were decreased in Cdc42‐CKO nerves, and these changes were rescued by NF2/merlin mutation in Cdc42‐CKO;NF2‐del double mutant mice. Thus, Cdc42 regulates SC radial sorting in vivo through NF2/merlin dependent signaling pathways, while Cdc42 modulation of myelin sheath folding is NF2/merlin independent. GLIA 2013;61:1906–1921     

腓骨肌萎缩症分子突变研究现状

腓骨肌萎缩症(charcot marie tooth disease,CMT)是一组高发病率的周围神经系统的单基因遗传病,具有临床和遗传异质性。可分为CMT1型,CMT2型,CMTX型和CMT4型。近些年随着分子遗传学和分子生物学的快速发展,已经发现了很多CMT的相关致病基因。主要包括外周髓鞘蛋白22基因、髓鞘蛋白零蛋白基因、间隙连接蛋白-32基因、驱动蛋白1B基因、Ras相关蛋白7基因、小分子热休克蛋白27基因等。本文就CMT相关致病基因研究现状作一综述。