생명과학회지 (Journal of Life Science)

  • 제29권7호
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  • Pages.800-808
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  • 2019
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  • 1225-9918(pISSN)
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  • 2287-3406(eISSN)
한국생명과학회 (Korean Society of Life Science)
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샤르코-마리-투스병 1A형(CMT1A)의 가족내 표현형적 이질성과 MIR149 SNP에 대한 연관성 연구

Association between MIR149 SNPs and Intrafamilial Phenotypic Variations of Charcot-Marie-Tooth Disease Type 1A

  • 최유진 (공주대학교 자연과학대학 생명과학과) ;
  • 이아진 (공주대학교 자연과학대학 생명과학과) ;
  • 남수현 (성균관대학교 의과대학 삼성서울병원 신경과) ;
  • 최병옥 (성균관대학교 의과대학 삼성서울병원 신경과) ;
  • 정기화 (공주대학교 자연과학대학 생명과학과)
  • Choi, Yu Jin (Department of Biological Sciences, Kongju National University) ;
  • Lee, Ah Jin (Department of Biological Sciences, Kongju National University) ;
  • Nam, Soo Hyun (Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Choi, Byung-Ok (Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Chung, Ki Wha (Department of Biological Sciences, Kongju National University)
  • 투고 : 2019.05.15
  • 심사 : 2019.06.11
  • 발행 : 2019.07.30
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초록

샤르코-마리-투스병(Charcot-Marie-Tooth disease: CMT)은 희귀 말초신경병의 그룹으로, 진행성 근육 약화 및 위축, 감각 소실, 상지 및 하지의 무반사 증상을 나타낸다. CMT1A는 PMP22 유전자가 존재하는 17p12 지역의 직렬 중복으로 발병하는데, 유전자형-표현형의 상관성이 느슨하여 2차 유전적 요인의 존재를 암시한다. 최근 MIR149의 rs71428439 (n.83A>G)와 rs2292832 (n.86T>C) 변이가 후기 발병 및 가벼운 증상의 표현형과 연관성이 있는 것으로 보고되었다. 본 연구는 CMT1A 기계내 임상적 표현형의 이질성이 MIR149의 SNP과 연관성이 있는지를 규명하기 위해 수행하였으며, 조사 대상으로는 가계내 표현형의 차이가 심한 6 CMT1A 대 가계를 대상으로 하였다. 그 결과, MIR149의 rs71428439와 s2292832 유전자형은 가족내의 늦은 발병과 약한 중증도의 유전적 요인으로 작용할 수 있음을 제시하였다. 특히, AG+GG (n.83A>G)와 TC+CC 유전자형(n.86T>C)은 발병 시기가 늦고 경미한 증상을 보였다. 운동신경 전기전도도(MNCV)는 MIR149 유전형과 연관이 없는 것으로 보였는데, 이러한 결과는 이전 연구와 일치한다. 따라서 본 연구는 MIR149의 rs71428439와 rs2292832 변이는 CMT1A 가계내 표현형적 이질성의 원인 중 하나로 작용할 가능성을 제시한다. 본 연구는 가계 내 증상의 차이가 심한 6 대가족을 사용하여 연구를 수행한 것은 의미가 크다고 여겨지며, 이런 결과는 CMT1A 환자의 분자 진단과 치료에 도움을 줄 수 있을 것으로 기대된다.

Charcot-Marie-Tooth disease (CMT) is a group of rare peripheral neuropathies characterized by progressive muscle weakness and atrophy and areflexia in the upper and lower extremities. The most common subtype of CMT is CMT1A, which is caused by a tandem duplication of the PMP22 gene in the 17p12 region. Patients with CMT1A show a loose genotype-phenotype correlation, which suggests the existence of secondary genetic or association factors. Recently, polymorphisms of rs71428439 (n.83A>G) and rs2292832 (n.86T>C) in the MIR149 have been reported to be associated with late onset and mild phenotypic CMT1A severity. The aim of this study was to examine the intrafamilial heterogeneities of clinical phenotypes according to the genotypes of these two SNPs in MIR149. For this study, we selected 6 large CMT1A families who showed a wide range of phenotypic variation. This study suggested that both SNPs were related to the onset age and severity in the dominant model. In particular, the AG+GG (n.83A>G) and TC+CC genotypes (n.86T>C) were associated to late onset and mild symptoms. Motor nerve conduction velocity (MNCV) was not related to the MIR149 genotypes. These results were consistent with the previous studies. Therefore, we suggest that the rs71428439 and rs2292832 variants in MIR149 may serve as genetic modifiers of CMT1A intrafamilial phenotypic heterogeneity, as they have a role in the unrelated patients. This is the first study to show an association using large families with variable clinical CMT1A phenotypes. The results will be helpful in the molecular diagnosis and treatment of patients with CMT1A.

키워드

SMGHBM_2019_v29n7_800_f0001.png 이미지

Fig. 1. Unequal crossover in 17p12 region containing PMP22 gene and location of 2 SNPs in premature miRNA149. (A) Occurrence of CMT1A duplication and HNPP deletion by recurrent unequal crossover in 17.12 region of 1.4 Mbp length (CMT1A: Charcot-Marie-Tooth disease type 1A; HNPP: hereditary neuropathy with liability to pressure palsies; SNP: single nucleotide polymorphism). (B) Schematic secondary structure of premature miRNA 149. Two SNPs of rs71428439 (n.83A>G) and rs2292832 (n.86T>C) were indicated by red arrows.

SMGHBM_2019_v29n7_800_f0002.png 이미지

Fig. 2. Pedigrees of six Korean CMT1A families with variable phenotypic variations. The filled squares and circles are affected individuals and unfilled squares or circles denoted unaffected individuals. Probands are indicated by arrows. At the bottom of each examined patient, onset age (years) and CMT neuropathy score (CMTNS) were provided at the upper line and genotypes of rs71428439 (n.83A>G) and rs2292832 (n.86T>C) are provided at the bottom line. (A) FC45, (B) FC152, (C) FC270, (D) FC272, (E) FC296, and (F) FC521.

SMGHBM_2019_v29n7_800_f0003.png 이미지

Fig. 3. Scatter plot of the onset age and clinical severities of the 38 CMT1A patients. The severity was measured by CMT neuropathy score (CMTNS).

SMGHBM_2019_v29n7_800_f0004.png 이미지

Fig. 4. Clinical phenotypes according to genotypes of MIR149 rs71428439 (n.83A>G). (A) Onset ages vs. genotyes. (B) CMTNS vs. genotyes. (C) MNVC vs. genotypes.

SMGHBM_2019_v29n7_800_f0005.png 이미지

Fig. 5. Clinical phenotypes according to genotypes of MIR149 rs2292832 (n.86T>C). (A) Onset ages vs. genotyes. (B) CMTNS vs. genotyes. (C) MNVC vs. genotypes.

Table 1. Base-line characteristics of the CMT1A families and control subjects

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Table 2. Primer sequences, concentration and labeling for multiplex PCR of 6 microsatellites

SMGHBM_2019_v29n7_800_t0002.png 이미지

Table 3. Genotype and allele frequencies of two MIR149 SNPs in CMT1A patients and controls

SMGHBM_2019_v29n7_800_t0003.png 이미지

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