• 대한소아치과학회지
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• 제43권3호
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• pp.299-305
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• 2016

본 연구는 서울대학교 치과병원 소아치과에 내원한 부분 무치증 환자를 대상으로 질환의 원인이 될 수 있는 돌연변이를 규명하고, 그 역할에 대하여 고찰하고자 하였다. 다수의 영구치 결손을 주소로 서울대학교 치과 병원에 내원 한 7세 여아와 어머니를 대상으로 구강검진 및 파노라마 방사선 촬영을 진행하였다. 연구 동의서를 받고, 유전자 검사를 위한 채혈을 시행하였다. PAX9 유전자의 모든 exon에 대해 특이적인 primer를 이용하여 중합효소 연쇄반응을 시행하였으며, 해당 산물을 정제하고 염기서열분석을 진행하였다. 결과는 NCBI Gene Bank와 대조하여 해당 영역의 돌연변이를 조사하였다. 7세 환아는 총 11개의 영구치 결손이 관찰되었으며, 어머니는 총 19개의 영구치 결손이 관찰되었다. 치아 결손 외에 손톱, 모발, 피부, 땀샘과 연관 된 다른 결함은 관찰되지 않았다. 유전자 분석 결과, PAX9의 exon 2 영역에서 nonsense mutation(c.184G>T, $p.Glu62^*$)을 확인하였으며, 대상자 모두에서 이형접합 돌연변이로 관찰되었다. 해당 돌연변이의 결과로 exon 2 내에서 전사 종결이 일어나게 되며, 발현 된 단백질은 정상 단백질에 비하여 280개의 아미노산이 짧은 상태로 발현된다고 추측할 수 있다. 결손된 부분은 paired box domain 및 DNA binding site 등 해당 단백질의 기능에 있어서 필수적인 영역을 포함하고 있으므로, 부분 무치증을 유발했을 가능성이 높다. 또는 해당 돌연변이의 전사체가 nonsense-mediated decay system(NMD system)에 의하여 분해됨으로써 haploinsufficiency를 유발하여 부분 무치증의 원인으로 작용했을 것으로 사료된다.

• Molecules and Cells
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• 제27권1호
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• pp.89-97
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• 2009

We investigate the molecular and cellular etiologies that underlie the deletion of the six amino acid residues (${\Delta}F323-Y328$; ${\Delta}FY$) in human torsin A (HtorA). The most common and severe mutation involved with early-onset torsion dystonia is a glutamic acid deletion (${\Delta}E$ 302/303; ${\Delta}E$) in HtorA which induces protein aggregates in neurons and cells. Even though ${\Delta}FY$ HtorA forms no protein clusters, flies expressing ${\Delta}FY$ HtorA in neurons or muscles manifested a similar but delayed onset of adult locomotor disability compared with flies expressing ${\Delta}E$ in HtorA. In addition, flies expressing ${\Delta}FY$ HtorA had fewer aberrant ultrastructures at synapses compared with flies expressing ${\Delta}E$ HtorA. Taken together, the ${\Delta}FY$ mutation in HtorA may be responsible for behavioral and anatomical aberrations in Drosophila.

• Journal of Genetic Medicine
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• 제16권1호
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• pp.19-22
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• 2019

The infantile convulsions and choreoathetosis (ICCA) syndrome is defined when two overlapping clinical features of benign familial infantile epilepsy (BFIE) and paroxysmal kinesigenic dyskinesia (PKD) are present in an individual or a family. Since the gene encoding proline-rich transmembrane protein 2 (PRRT2) was first identified in Han Chinese families with PKD, mutations of PRRT2 have additionally been reported in patients with BFIE and ICCA. We attempted to identify the genetic etiology in an ICCA family where the proband, her elder sister, and a maternal male cousin had BFIE, and her mother had PKD. Whole-exome sequencing performed in the proband and her sister and mother identified a novel pathogenic mutation of PRRT2 (c.640delinsCC; p.Ala214ProfsTer11), which was verified by Sanger sequencing. This frameshift PRRT2 mutation located near the genetic hot spot of base 649_650 results in the premature termination of the protein, as do most previously reported mutations in BFIE, ICCA, and PKD.

• Molecules and Cells
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• 제42권1호
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• pp.8-16
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• 2019

Mutations in the ${\beta}-catenin$ gene (CTNNB1) have been implicated in the pathogenesis of some cancers. The recent development of cancer genome databases has facilitated comprehensive and focused analyses on the mutation status of cancer-related genes. We have used these databases to analyze the CTNNB1 mutations assembled from different tumor types. High incidences of CTNNB1 mutations were detected in endometrial, liver, and colorectal cancers. This finding agrees with the oncogenic role of aberrantly activated ${\beta}-catenin$ in epithelial cells. Elevated frequencies of missense mutations were found in the exon 3 of CTNNB1, which is responsible for encoding the regulatory amino acids at the N-terminal region of the protein. In the case of metastatic colorectal cancers, in-frame deletions were revealed in the region spanning exon 3. Thus, exon 3 of CTNNB1 can be considered to be a mutation hotspot in these cancers. Since the N-terminal region of the ${\beta}-catenin$ protein forms a flexible structure, many questions arise regarding the structural and functional impacts of hotspot mutations. Clinical identification of hotspot mutations could provide the mechanistic basis for an oncogenic role of mutant ${\beta}-catenin$ proteins in cancer cells. Furthermore, a systematic understanding of tumor-driving hotspot mutations could open new avenues for precision oncology.

• Journal of Interdisciplinary Genomics
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• 제4권1호
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• pp.15-18
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• 2022

Hemophilia A is a rare X-linked congenital deficiency of clotting factor VIII (FVIII) that is traditionally diagnosed by measuring FVIII activity. Various mutations of the FVIII gene have been reported and they influence on the FVIII protein structure. A deficiency of or reduction in FVIII protein manifests as spontaneous or induced bleeding depending on the disease severity. Mutations of the FVIII gene provide important information on the severity of disease and inhibitor development. FVIII mutations also affect the discrepant activities found using different FVIII assays. FVIII activity is affected differently depending on the mutation site. Long-range PCR is commonly used to detect intron 22 inversion, the most common mutation in severe hemophilia. However, point mutations are also common in patients with hemophilia, and direct Sanger sequencing and copy number variant analysis are being used to screen for full mutations in the FVIII gene. Advances in molecular genetic methods, such as next-generation sequencing, may enable accurate analysis of mutations in the factor VIII gene, which may be useful in the diagnosis of mild to moderate hemophilia. Genetic analysis is also useful in diagnosing carriers and managing bleeding control. This review discusses the current knowledge about mutations in hemophilia and focuses on the clinical aspects associated with these mutations and the importance of genetic analysis.

• BMB Reports
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• 제34권1호
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• pp.1-7
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• 2001

Structural and physical properties of type wild type and various selected mutants of the vnd/NK-2 homeodomain, the protein product of the homeobox, and the implication in genetic disease are reviewed. The structure, dynamics and thermodynamics have been Investigated by NMR and by calorimetry. The interactions responsible for the nucleotide sequence-specific binding of the homeodomain to its consensus DNA binding site have been identified. There is a strong correlation between significant structural alterations within the homeodomain or its DNA complex and the appearance of genetic disease. Mutations in positions known to be important in genetic disease have been examined carefully For example, mutation of position 52 of vnd/NK-2 results in a significant structural modification and mutation of position 54 alters the DNA binding specificity and amity The $^{15}N$ relaxation behavior and heteronuclear Overhauser effect data was used to characterize and describe the protein backbone dynamics. These studies were carried out on the wild type and the double mutant proteins both in the free and in the DNA bound states. Finally, the thermodynamic properties associated with DNA binding are described for the vnd/NK-2 homeodomain. These thermodynamic measurements reinforce the hypothesis that water structure around a protein and around DNA significantly contribute to the protein-DNA binding behavior. The results, taken together, demonstrate that structure and dynamic studies of proteins combined with thermodynamic measurements provide a significantly more complete picture of the solution behavior than the individual studies.

• Bulletin of the Korean Chemical Society
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• 제31권10호
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• pp.2877-2883
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• 2010

The folding kinetics of $WT^*$ ubiquitin variant with valine to alanine mutation at sequence position 26 (HubWA) was studied by stopped-flow fluorescence spectroscopy. While unfolding kinetics showed a single exponential phase, refolding reaction showed three exponential phases. The semi-logarithmic plot of urea concentration vs. rate constant for the first phase showed v-shape pattern while the second phase showed v-shape with roll-over effect at low urea concentration. The rate constant and the amplitude of the third phase were constant throughout the urea concentrations, suggesting that this phase represents parallel process due to the configurational isomerization. Interestingly, the first and second phases appeared to be coupled since the amplitude of the second phase increased at the expense of the amplitude of the first phase in increasing urea concentrations. This observation together with the roll-over effect in the second folding phase indicates the presence of intermediate state during the folding reaction of HubWA. Quantitative analysis of Hub-WA folding kinetics indicated that this intermediate state is on the folding pathway. Folding kinetics measurement of a mutant HubWA with hydrophobic core residue mutation, Val to Ala at residue position 17, suggested that the intermediate state has significant amount of native interactions, supporting the interpretation that the intermediate is on the folding pathway. It is considered that HubWA is a useful model protein to study the contribution of residues to protein folding process using folding kinetics measurements in conjunction with protein engineering.

• 한국발생생물학회:학술대회논문집
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• 한국발생생물학회 2003년도 제3회 국제심포지움 및 학술대회
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• pp.94-94
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• 2003

Rotavirus는 유아나 어린아이들에게 가장 일반적으로 나타나는 심한 위장염의 원인자이며 설사로 인한 심한 탈수 증세를 일으켜 급속히 성장하는 유아의 균형적인 영양 공급을 방해함으로써 유아들의 발육과 성장 그리고 심하면 생명에 커다란 영향을 미치게 된다. 한편 모유로 키운 유아들은 설사병의 낮은 발병율과 연관이 있었다. 특히 모유의 뮤신 복합체는 rotavirus에 특이적으로 결합하여 항 바이러스활동을 보여주는 것으로 나타났다. 이러한 배경에서 본 연구는 human breast tissue로부터 lactadherin의 cloning 및 sequence 분석을 통하여 유전자의 다양성을 조사하기로 하였다. 한국 여성 9명의 유두 근처 조직에서 lactadherin을 cloning하여 그 sequence를 보고 된 서양여성의 염기서열과 비교 분석결과 여러 곳에서 single nucleotide variation이 발견되었고 본 연구에서 클론한 lactadherin(31bp-1518bp)의 염기서열과 보고된 서양여성 lactadherin gene의 SNP와 비교하였을 때 8개의 SNP중 3부분만이 일치한다는 것을 확인하였다. 또한 같은 조직중 정상 조직과 암 조직 부분에서 각각 lactadherin을 클론하여 염기서열을 비교 분석하였는데 정상 조직에서 2곳의 silent mutation있었고 암조직에서 2곳의 mutation과 1곳의 silent mutation을 발견하였으며 전체 적으로 정상조직과 암 조직 부분에서 lactadherin을 clone하여 염기서열을 분석해본 결과 암조직일수록 유전자의 변이 비율이 높다는 것을 알 수 있었다. 그리고 동일한 염기서열 상에서 많은 변이가 일어났는데 286dp(A->C), 1418dp(G->C)은 mutation이었고 327dp (A->G), 454(C->T)은 silent mutation이었다. 그 외 DNA상에서 여러 부근에 변이가 존재하였는데 이 결과로 보아 coding region에 위치한 cSNP 중 amino acid 변화를 일으켜 protein structure 또는 function에 영향을 줄 수 있는 non-synonymous cSNP 일 것으로 예상되어지며 natural selection의 영향을 받고 있음을 암시하고 있다. 본 연구에서 관찰되어진 각각의 염기 서열의 변이는 한국 사람이 가지는 lactadherin gene의 cSNP의 일부라고 판단하였다.

• Clinical and Experimental Pediatrics
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• 제54권4호
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• pp.179-182
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• 2011

Transient neonatal diabetes mellitus (TNDM) is a rare form of diabetes mellitus that presents within the first 6 months of life with remission in infancy or early childhood. TNDM is mainly caused by anomalies in the imprinted region on chromosome 6q24; however, recently, mutations in the ABCC8 gene, which encodes sulfonylurea receptor 1 (SUR1), have also been implicated in TNDM. Herein, we present the case of a male child with TNDM whose mutational analysis revealed a heterozygous c.3547C>T substitution in the ABCC8 gene, leading to an Arg1183Trp mutation in the SUR1 protein. The parents were clinically unaffected and did not show a mutation in the ABCC8 gene. This is the first case of a de novo ABCC8 gene mutation in a Korean patient with TNDM. The patient was initially treated with insulin and successfully switched to sulfonylurea therapy at 14 months of age. Remission of diabetes had occurred at the age of 16 months. Currently, the patient is 21 months old and is euglycemic without any insulin or oral hypoglycemic agents. His growth and physical development are normal, and there are no delays in achieving neurological and developmental milestones.

• Genomics & Informatics
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• 제1권2호
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• pp.75-79
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• 2003

Every protein can be characterized by either a distinct motif or a combination of motifs. Nevertheless, little is known about the relationships among (more than two) the motifs. Some of the proteins in the world are share motifs for evolutional or other biological benefits - they can save energy, time and resource for controlling and managing a variety of proteins. In some cases of motifs, the tendency is quite common and they can act the 'hub' motif of a network of the motif associations. The hubs are structurally and functionally important in themselves and also important in disease-related mutations. They will be highly resistant mutation to conserve their functions. But, in case of the a rare mutation, mutations on the position of hub can more easily cause fatal diseases.