Novel amyloid precursor protein mutation, Val669Leu (“Seoul <i>APP</i>”), in a Korean patient with early-onset Alzheimer's disease

Bagyinszky, Eva,Kang, Min Ju,Van Giau, Vo,Shim, KyuHwan,Pyun, Jung-Min,Suh, Jeewon,An, Seong Soo A.,Kim, SangYun Elsevier 2019 NEUROBIOLOGY OF AGING Vol.84 No.-

<P><B>Abstract</B></P> <P>In this study, a novel mutation in <I>APP</I> gene, Val669Leu (“Seoul <I>APP</I>”), was reported in a Korean female patient with Alzheimer's disease. She developed cognitive decline at 56 years of age, and her memory declined rapidly over one-year period from her 1st visit to the hospital. Her Mini-Mental State Examination scores dropped from 25/30 to 13/30. Two years later, she developed parkinsonian features, myoclonic jerk, and generalized seizure. As the disease progressed, aggravated diffuse brain atrophy and small-vessel ischemic lesion was also observed, and she became mute and vegetative in 4 years from the symptom onset. Magnetic resonance imaging showed mild medial temporal lobe and hippocampal atrophy, and 18F-fluoro-deoxyglucose positron emission tomography showed bilateral temporoparietal hypometabolism. Plasma amyloid oligomer analysis revealed highly elevated Aβ oligomers levels in the proband patient. Family history revealed positive without biochemical confirmation because family members testified similar type of cognitive decline from the proband's mother and one of her aunt/uncle. Her half-siblings did not present any signs of memory impairment. Sanger sequencing of the proband patient revealed a novel mutation in <I>APP</I> gene, Val669Leu, but mutation was not found in her unaffected half-sisters. A designed algorithm by Guerreiro et al. on early-onset Alzheimer's disease–associated mutations suggested the mutation as possibly pathogenic mutation. On the other hand, PolyPhen2 and SIFT tools suggested as otherwise. Since the mutation was located nearby the β-secretase cleavage site of APP, right next to the Swedish APP (Lys,Met670/671Asn,Leu) mutation, it was named as “Seoul <I>APP”</I> mutation. 3D modeling revealed that this mutation could result in significant changes in loop orientation of APP and also its intramolecular interactions. Hence, a novel <I>APP</I> Val669Leu mutation could alter the binding interactions between APP and β-secretase, which may influence the Aβ40 and Aβ42 generations.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A novel variant in APP, Val669Leu, was found in a Korean patient, named Seoul APP. </LI> <LI> Proband patient developed disease phenotype in her 50s. </LI> <LI> Family history may be positive, and mutation may segregate with disease. </LI> <LI> Mutation is located nearby the beta-secretase site of APP, and potentially disturbs the enzyme mechanism. </LI> </UL> </P>

A Novel Frameshift Mutation of SLC26A4 in a Korean Family With Nonsyndromic Hearing Loss and Enlarged Vestibular Aqueduct

보름사공,백정인,이규엽,김언경 대한이비인후과학회 2017 Clinical and Experimental Otorhinolaryngology Vol.10 No.1

Objectives. We aimed to identify the causative mutation for siblings in a Korean family with nonsyndromic hearing loss (HL) and enlarged vestibular aqueduct (EVA). The siblings were a 19-year-old female with bilateral profound HL and an 11-year-old male with bilateral moderately severe HL. Methods. We extracted genomic DNA from blood samples of the siblings with HL, their parents, and 100 controls. We performed mutation analysis for SLC26A4 using direct sequencing. Results. The two siblings were compound heterozygotes with the novel mutation p.I713LfsX8 and the previously described mutation p.H723R. Their parents had heterozygous mono-allelic mutations. Father had p.I713LfsX8 mutation as heterozygous, and mother had p.H723R mutation as heterozygous. However, novel mutation p.I713LfsX8 was not detected in 100 unrelated controls. Conclusion. Both mutations identified in this study were located in the sulfate transporter and anti-sigma factor antagonist domain, the core region for membrane targeting of SulP/SLC26 anion transporters, which strongly suggests that failure in membrane trafficking by SLC26A4 is a direct cause of HL in this family. Our study could therefore provide a foundation for further investigations elucidating the SLC26A4-related mechanisms of HL.

Identification a novel de novo RUNX2 frameshift mutation associated with cleidocranial dysplasia

Gong Lei,Odilov Bekzod,Han Feng,Liu Fuqiang,Sun Yujing,Zhang Ningxin,Zuo Xiaolin,Yang Jiaojiao,Wang Shouyu,Hou Xinguo,Ren Jianmin 한국유전학회 2022 Genes & Genomics Vol.44 No.6

Background: Cleidocranial dysplasia (CCD) is a rare genetic disorder affecting bone and cartilage development. Clinical features of CCD comprise short stature, delayed ossification of craniofacial structures with numerous Wormian bones, underdeveloped or aplastic clavicles and multiple dental anomalies. Several studies have revealed that CCD development is strongly linked with different mutations in runt-related transcription factor 2 (RUNX2) gene. Objective: Identification and functional characterization of RUNX2 mutation associated with CCD. Methods: We performed genetic testing of a patient with CCD using whole exome sequencing and found a novel RUNX2 frameshift mutation: c.1550delT in a sporadic case. We also compared the functional activity of the mutant and wild-type RUNX2 through immunofluorescence microscopy and osteocalcin promoter luciferase assay. Results: We found a novel RUNX2 frameshift mutation, c.1550delT (p.Trp518Glyfs*60). Both mutant RUNX2 and wild-type RUNX2 protein were similarly confined in the nuclei. The novel mutation caused abrogative transactivation activity of RUNX2 on osteocalcin promoter. Conclusions: We explored a novel RUNX2 deletion/frameshift mutation in a sporadic CCD patient. This finding suggests that the VWRPY domain may play a key role in RUNX2 transactivation ability.

Sporadic epidermolysis bullosa simplex with a novel KRT14 mutation

( Young Wook Ko ),( Tae Lim Kim ),( Won Seon Koh ),( Jeong Eun Kim ),( Jooyeon Ko ),( Young Suck Ro ) 대한피부과학회 2018 대한피부과학회 학술발표대회집 Vol.70 No.1

Epidermolysis bullosa simplex (EBS) is a rare genodermatosis characterized by mechanical stress-induced blistering of the skin. Its pathogenesis is mainly associated with defects of attachment of basal keratinocytes to the underlying dermis, resulted from keratin (KRT) 5 and KRT 14 mutation. We experienced a sporadic case of EBS with a novel KRT 14 mutation. A 1-day-old female full-term newborn presented with multiple bullae and erosions mainly on hands and feet. She did not show signs of other systemic diseases. Familial history of dermatologic diseases was absent. The histopathologic examination showed intraepidermal cleft. Direct immunofluorescence finding was negative. Electromicroscopy showed that the level of cleavage was low within the basal keratinocytes, just above the level of the hemidesmosomes and keratin clumps were not observed. Additional genetic analysis by exon sequencing revealed a novel de novo heterozygous missense mutation c.369T>G (p.Asn123Lys) in KRT14 gene. On the other hand, other family members including parents and her brother did not show any abnormalities in KRT14 gene. From these findings, she was diagnosed with EBS. She is receiving conservative treatment and is being followed-up for 6 months without serious complications. Herein, we report a rare case of neonatal EBS with de novo KRT14 gene mutation, which has been only once reported in the literatures to our knowledge.

A novel mutation in the DNMT1 gene in a patient presenting with pure cerebellar ataxia

Algahtani, Hussein,Shirah, Bader Korean Society of Medical Genetics and Genomics 2017 대한의학유전학회지 Vol.14 No.2

Mutations in the DNA methyltransferase 1 gene (DNMT1) were reported to cause two phenotypes: OMIM 604121 and OMIM 614116. The first phenotype includes autosomal dominant cerebellar ataxia, deafness, and narcolepsy, which were reported to be caused by mutations in exon 21. The second phenotype includes hereditary sensory and autonomic neuropathy type 1E, which was suggested to be caused by mutations in exon 20 and 21. In this article, we report a novel heterozygous missense variant c.898A>C, p.(Lys300Gln) in exon 12 of DNMT1 in a young woman who presented with pure cerebellar ataxia. This report indicates that a mutation in exon 12 may lead to pure cerebellar ataxia. Another possibility is that the patient is currently in an early stage of the disease, and as the disease progresses, she will have more manifestations. To confirm or exclude this possibility, a subsequent follow-up study reporting the disease progression in this patient may be needed. Further reports of cases with the same mutation are needed to confirm the phenotype of this mutation.

A novel mutation in the DNMT1 gene in a patient presenting with pure cerebellar ataxia

Hussein Algahtani,Bader Shirah 대한의학유전학회 2017 대한의학유전학회지 Vol.14 No.2

Mutations in the DNA methyltransferase 1 gene (DNMT1) were reported to cause two phenotypes: OMIM 604121 and OMIM 614116. The first phenotype includes autosomal dominant cerebellar ataxia, deafness, and narcolepsy, which were reported to be caused by mutations in exon 21. The second phenotype includes hereditary sensory and autonomic neuropathy type 1E, which was suggested to be caused by mutations in exon 20 and 21. In this article, we report a novel heterozygous missense variant c.898A>C, p.(Lys300Gln) in exon 12 of DNMT1 in a young woman who presented with pure cerebellar ataxia. This report indicates that a mutation in exon 12 may lead to pure cerebellar ataxia. Another possibility is that the patient is currently in an early stage of the disease, and as the disease progresses, she will have more manifestations. To confirm or exclude this possibility, a subsequent follow-up study reporting the disease progression in this patient may be needed. Further reports of cases with the same mutation are needed to confirm the phenotype of this mutation.

Compound Heterozygosity for Two Novel SLC26A4 Mutations in a Large Iranian Pedigree with Pendred Syndrome

Nasrin Yazdanpanahi,Mohammad Amin Tabatabaiefar,Effat Farrokhi,Narges Abdian,Nader Bagheri,Shirin Shahbazi,Zahra Noormohammadi,Morteza Hashemzadeh Chaleshtori 대한이비인후과학회 2013 Clinical and Experimental Otorhinolaryngology Vol.6 No.4

Objectives. The aim of this study was to detect the genetic cause of deafness in a large Iranian family. Due to the importance of SLC26A4 in causing hearing loss, information about the gene mutations can be beneficial in molecular detection and management of deaf patients. Methods. We investigated the genetic etiology in a large consanguineous family with 9 deaf patients from Fars province of Iran with no GJB2 mutations. Initially, linkage analysis was performed by four DFNB4 short tandem repeat markers. The result showed linkage to DFNB4 locus. Following that, DNA sequencing of all 21 exons, their adjacent intronic sequences and the promoter of SLC26A4 was carried out for mutation detection. Results. Two novel mutations (c.863-864insT and c.881-882delAC) were identified in exon 7 of the gene, in both homozygous and compound heterozygous state in patients. Conclusion. Our results supported the importance of the SLC26A4 mutations in the etiology of hearing loss among the Iranian patients and therefore its mutation screening should be considered after GJB2 in the molecular diagnostics of hearing loss, especially when enlarged vestibular aqueduct or goiter is detected.

Four novel mutations in the androgen receptor gene from Vietnamese patients with androgen insensitivity syndrome

Nguyen Thu Hien,Nguyen Duc Quan,Kim Lien Nguyen Thi,Thi Thanh Ngan Nguyen,Nguyen Thi Phuong Mai,Tran Ngoc Dung,Nguyen Huy Hoang 한국유전학회 2023 Genes & Genomics Vol.45 No.4

Background Androgens and androgen receptor (AR) are critical regulators of the masculinization process in male sexual development. The absence of a functioning AR results in the development of the androgen insensitivity syndrome (AIS), a rare disorder of sexual development (DSD) characterized by the external genitalia feminization, gynecomastia, and impaired spermatogenesis. Objective To determine the AR gene mutations associated with male DSD in four unrelated Vietnamese patients. Methods To detect the disease-causing mutations, whole exome sequencing (WES) was performed on four patients diagnosed with AIS. Sanger sequencing was then used for validation of the identified mutations. Finally, 12 web-based tools, three-dimensional protein modeling software, and the guidelines issued by the American College of Medical Genetics and Genomics were used to assess the potential pathogenicity of these mutations. Results Four distinct novel mutations, namely c.1834T > A (p.Cys612Ser), c.2122 C > G (p.Leu708Val), c.2630T > G (p.Phe877Cys), and c.2641 C > A (p.Leu881Met) in the AR gene, were identified in four AIS patients using WES. The in silico analysis results revealed that the Cys612, Leu708, Phe877, and Leu881 sites are important for an appropriate response to androgens of the AR, and mutation at these sites can have adverse effects on the AR functions, androgen–AR interaction, and AR signaling pathway. Conclusions WES and in silico analyses strongly suggested that four novel AR mutations are pathogenic and have led to the development of AIS in the four Vietnamese patients under consideration.

A Novel Mutation of the Steroid 5-Alpha Reductase Type 2 (SRD5A2) Gene in a Korean Newborn with Ambiguous Genitalia

김란희,김수영,유한욱,김구환,전종근 대한소아내분비학회 2010 Annals of Pediatirc Endocrinology & Metabolism Vol.15 No.2

The term “disorders of sex development” (DSD) includes congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical. Steroid 5-alpha reductase type 2 deficiency (5α-RD2) is an uncommon autosomal recessive disorder of sexual differentiation. It results from impaired conversion of testosterone (T) to dihydrotestosterone (DHT) due to mutations in the steroid 5-alpha reductase type 2 (SRD5A2) gene. It is characterized by a lack of masculinization in XY individuals due to failure to convert testosterone to dihydrotestosterone. More than 40 mutations have been reported in all five exons of the SRD5A2 gene. Here, we report on a 17-day-old Korean newborn who was confirmed to have 5α-RD2 by SRD5A2 gene analysis. He manifested micropenis, hypospadia and bilateral cryptorchidism without skin hyperpigmentation. T/DHT ratio after human chorionic gonadotropin (hCG) stimulation was slightly increased and genetic analysis of SRD5A2 revealed compound heterozygous mutations, c.657C˃G (p.Phe219Leu) and c.656del (p.Phe219SerfsX60), the former of which is a novel mutation. We report a novel SRD5A2 gene mutation in a Korean newborn with 5α-RD2.

A novel mutation of CLCNKB in a Korean patient of mixed phenotype of Bartter-Gitelman syndrome

Hee-Won Cho,Sang Taek Lee,Hee Yeon Cho,Hae Il Cheong 대한소아청소년과학회 2016 Clinical and Experimental Pediatrics (CEP) Vol.59 No.no.sup1

Bartter syndrome (BS) is an inherited renal tubular disorder characterized by low or normal blood pressure, hypokalemic metabolic alkalosis, and hyperreninemic hyperaldosteronism. Type III BS is caused by loss-of-function mutations in CLCNKB encoding basolateral ClC-Kb. The clinical phenotype of patients with CLCNKB mutations has been known to be highly variable, and cases that are difficult to categorize as type III BS or other hereditary tubulopathies, such as Gitelman syndrome, have been rarely reported. We report a case of a 10-year-old Korean boy with atypical clinical findings caused by a novel CLCNKB mutation. The boy showed intermittent muscle cramps with laboratory findings of hypokalemia, severe hypomagnesemia, and nephrocalcinosis. These findings were not fully compatible with those observed in cases of BS or Gitelman syndrome. The CLCNKB mutation analysis revealed a heterozygous c.139G>A transition in exon 13 [p.Gly(GGG)465Glu(GAG)]. This change is not a known mutation; however, the clinical findings and in silico prediction results indicated that it is the underlying cause of his presentation.