A novel presenilin 1 mutation, I202F occurring at a previously predicted pathogenic site causing autosomal dominant Alzheimer's disease

We report a novel presenilin-1 (PSEN1) mutation, I202F occurring in a Welsh kindred with familial Alzheimer's disease. The average age at onset was 53 years. The I202F mutation occurs in alignment with previously reported PSEN1 mutations in the fourth transmembrane domain and confirms that PSEN1 mutations line up along transmembrane alpha-helices.     

Identification of PSEN1 and APP gene mutations in Korean patients with early-onset Alzheimer's disease

Although mutations in three genes, amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), have been identified as genetic causes of early-onset Alzheimer s disease (EOAD), there has been a single report on a PSEN1 mutation in Koreans. In the present study, we performed a genetic analysis of six Korean patients with EOAD. Direct sequencing analysis of the APP, PSEN1 and PSEN2 genes revealed two different mutations of the PSEN1 gene (G206S and M233T) and one mutation of the APP gene (V715M) in three patients with age-at-onset of 34, 35, and 42 yr, respectively. In addition, two patients with age-at-onset of 55 and 62 yr, respectively, were homozygous for APOE epsilon 4 allele. One woman had no genetic alterations. These findings suggest that PSEN1 and APP gene mutations may not be uncommon in Korean patients with EOAD and that genetic analysis should be provided to EOAD patients not only for the identification of their genetic causes but also for the appropriate genetic counseling.     

Alzheimer病患者早老素-1基因第5外显子突变特征分析

目的　探讨早老素-1 基因突变在散发性Alzheim er 病(sporadic Alzheim er's disease, SAD)患者发病机理中的作用。方法　应用聚合酶链反应-单链构象多态性(polym erase chain reaction-singlestrand conform ation polym orphsim ,PCR-SSCP)及DNA 直接测序技术检测68 例SAD 患者和65 名正常老年人的早老素-1 基因第5 外显子。结果　发现68 例SAD患者中有4 例患者的SSCP发生泳动异常,DNA 序列分析发现:这4 例SAD 患者的130 号密码子发生了CTG→ATG 错义突变(388 位点发生C→A突变),使氨基酸由亮氨酸变为蛋氨酸(Leu 130 Met);157 号密码子发生了GTG→CTG 错义突变(469 位点发生G→C突变),使氨基酸由缬氨酸变为亮氨酸(Val157 Leu);有11 例患者的SSCP表现为一条单链电泳迁移率明显增快,DNA 序列分析发现:这11 例SAD患者的130 号密码子发生了CTG→ATG 错义突变(388 位点发生C→A 突变),使氨基酸由亮氨酸变为蛋氨酸(Leu 130 Met);154 号密码子发生了TGC→TGT 同义突变(462 位点发生C→T)突变。结论　我们发现在SAD患者中存在早老素-1 基因第5 外显子突变,该突变点可能为中国人SAD 患者早老素基因突变点之一。     

A novel PSEN1 gene mutation (L235R) associated with familial early-onset Alzheimer's disease

Mutations in the presenilin 1 (PSEN1) gene are the most frequent cause of familial Alzheimer's disease (AD), with at least 182 different mutations published to date. We report a 48-year-old woman (age at onset 47 years) who presented a progressive alteration of episodic memory, spatial disorientation, apathy, language disturbances and neglect of personal care. Her MMSE score was 20/30. The patient presented an unusually rapid deterioration and at 6 months follow-up her cognitive and functional status had worsened considerably (MMSE score of 11). Cranial MRI showed a bilateral atrophy with temporal and parietal predominance and the quantification of AD CSF biomarkers showed the typical AD signature. Family history evidenced an autosomal dominant pattern of inheritance. Mutational screening was performed by direct sequencing of exons 3-12 of PSEN1. The patient presented the 3/3 APOE genotype. Genetic analysis revealed a nucleotide substitution in exon 7 of PSEN1 gene, producing a missense mutation in codon 235 from leucine amino acid to arginine (L235R). This amino acid is conserved between presenilin-1 and presenilin-2 proteins. The L235R mutation had not been previously reported, although other mutations in the same residue have also been associated with familial early-onset AD, providing support for the importance of this residue for the presenilin-1 function.     

Identification of three novel mutations and a high frequency of the Arg778Leu mutation in Korean patients with Wilson disease

Four mutations—R778L, A874V, L1083F, and 2304delC—in the copper-transporting enzyme, P-type ATPase (ATP7B), were identified in Korean Patients with Wilson disease. Arg778Leu, the most frequently reported mutation of this enzyme, was found in six of eight unrelated patients studied, an allele frequency of 37.5%, which is considerably higher than those in other Asian populations. The novel single nucleotide deletion, 2304delC, was found in one patient. Since a mutation at cDNA nucleotide 2302 (2302insC) had been previously described, this region of the ATP7B gene may be susceptible to gene rearrangements causing Wilson disease. Hum Mutat 11:275–278, 1998. © 1998 Wiley-Liss, Inc.     

Alteration of acylphosphatase levels in familial Alzheimer''s disease fibroblasts with presenilin gene mutations

Acylphosphatase (ATPase), an enzyme that modulates the activity of Ca²⁺-ATPase by hydrolysing its phosphorylated moiety, has been found to be significantly higher in cultured skin fibroblasts from donors affected by early onset familial Alzheimer's disease (EOFAD) with PS-1 and PS-2 gene mutations. Of the two known isoenzymes of acylphosphatase, only the erythrocyte one accounts for the total increase in activity. No relevant alteration was observed in phosphotyrosine phosphatase activity (PTPase), in Ca²⁺-ATPase and Na⁺,K⁺-ATPase activities of the same cells as compared to age-matched controls. This finding could suggest a possible explanation for the calcium-dependent biochemical alterations previously described in Alzheimer's disease fibroblasts.     

A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a Japanese family with presenile familial Alzheimer's disease

Over fifty missense mutations in the presenilin‐1 (PSEN1) gene have been reported in families with presenile familial Alzheimer's disease (FAD). We describe a novel missense mutation (G209R) within the predicted fourth transmembrane domain of the PSEN1 in a Japanese family with presenile FAD. The affected cases showed similar disease histories with the mean age at onset of 49.6 ± 3.1 years and rapid progressive dementia characterized by memory impairment, amnestic aphasia, disorientation and personality change, but lacking parietal focal symptoms such as apraxia or agnosia. Compared with the previously reported cases of same Gly209 mutation (G209V), the clinical features of the G209R‐FAD cases appear to be less critical than those of G209V‐FAD cases, although the Gly to Arg mutation is considered to be less conservative than the Gly to Val mutation. These findings may suggest the possible existence of other genetic and/or environmental factors or the possibility that these two different Gly209 mutations may underlie different pathomechanisms in the development of presenile FAD. Hum Mutat 14:90, 1999. © 1999 Wiley‐Liss, Inc.     

Novel presenilin 1 variant (P117A) causing Alzheimer's disease in the fourth decade of life

Over 160 rare genetic variants in presenilin 1 (PSEN1) are known to cause Alzheimer's disease (AD). In this study we screened a family with early-onset AD for mutations in PSEN1 using direct DNA sequencing. We identified a novel PSEN1 genetic variant which results in the substitution of a Proline with an Alanine at codon 117 (P117A). The P117A variant was present in all demented individuals and fifty percent of at risk individuals. This variant occurs at a site where three other disease-causing variants have been previously observed. In vitro functional studies demonstrate that the P117A variant results in an altered Abeta42/total Abeta ratio consistent with an AD causing mutation. The P117A variant is a novel mutation in PSEN1, which causes early-onset AD in an autosomal dominant manner.     

家族性阿尔茨海默病早老素-1基因突变研究

目的　探讨早老素 - 1(presenilin- 1,PS- 1)基因的突变在家族性痴呆患者发病机理中的作用。方法　应用聚合酶链反应 -单链构象多态性 (polymerase chain reaction- single strand conformationpolymorphism,PCR- SSCP)和 DNA测序技术检测 2例家族性阿尔茨海默病型痴呆 (familial Alzheimer′sdisease,FAD)患者、5 3例散发性阿尔茨海默病型痴呆 (sporadic Alzheimer′s disease,SAD)患者、6 0例血管性痴呆 (vascular dementia,VD)患者及 90名健康老年人 PS- 1基因第 6外显子。结果　DNA测序在 SSCP泳动异常标本中发现 112 3位点和 130 0位点发生错义突变 ,其中 ,FAD患者 2例均在 130 0位点发生突变 ,SAD组 2例在 112 3位点发生突变、2例在 130 0位点突变 ,VD组 1例在 112 3位点发生突变 ;112 3位点发生 C→G突变 (Cys2 3Trp) ,130 0位点发生 A→C突变 (Asp2 0 0 Ala)。结论　FAD及 SAD患者存在 PS-1基因第 6外显子突变 ,上述两个突变位点均位于早老素蛋白的重要功能区 ,此突变可能为病理性突变。     

Novel missense mutation (Leu466Arg) of the DAX1 gene in a patient with X-linked congenital adrenal hypoplasia

We identified a DAX1 missense mutation, a substitution of arginine for leucine at codon 466 (Leu466Arg), in an infant with X-linked congenital adrenal hypoplasia (AHC). A heterozygous substitution, Leu466Arg, was also identified in his mother and sister. Since leucine at position 466 is well conserved among other orphan nuclear hormone receptor superfamilies and Leu466Arg was not detected among 50 normal Japanese control individuals, the mutation is most likely responsible for X-linked AHC. It is interesting to note that Leu466Arg among all mutations ever reported is located at the most C-terminal region of the DAX-1 protein. Most mutations identified previously were located in the C-terminal presumptive ligand binding domain. Hence, the C-terminal end of the DAX-1 protein may play an important role in the biological function, such as in normal adrenal embryogenesis. Am. J. Med. Genet. 84:87–89, 1999. © 1999 Wiley-Liss, Inc.     

A novel presenilin 1 mutation (Ser169del) in a Chinese family with early-onset Alzheimer's disease

Early-onset familial Alzheimer's disease (EOFAD) has been associated with mutations in three genes, of which presenilin 1 (PSEN1) mutations are the most frequent. Here we report a novel PSEN1 mutation in a Chinese family with autosomal dominant Alzheimer's disease with an onset age in the early 40s. Molecular genetic analysis showed a 507-509delATC mutation at codon 169, leading to the deletion of serine in residue 169 (Ser169del). The amnestic presentation and absence of other features contrast with the other two mutations at codon 169 which have been associated with myoclonic jerks and seizures.     

Brachydactyly type A1 associated with unusual radiological findings and a novel Arg158Cys mutation in the Indian hedgehog (IHH) gene

Brachydactyly type A1 (BDA1; MIM 112500) is characterized by shortness or absence of the middle phalanx of the hands and feet. The condition is caused by heterozygous mutations in the Indian hedgehog (IHH) gene or a yet unidentified gene on chromosome 5p13. We investigated six affected members of a large Swedish family segregating autosomal dominant brachymesophalangia. Affected individuals show hypoplasia of the ulnar styloid processes, ulna minus, osteoarthritis, normal length of all distal phalanges and shortening or absence of the middle phalanges. Stationary ossicles or sesamoid bones were observed at the metacarpal heads in all patients. Genetic analysis of the family showed that the IHH-gene was linked to the disease (Z_max 3.42 at theta 0.00) and sequence analysis of IHH revealed a novel c.472C > T transition in all affected family members. The mutation results in a p.158Arg > Cys substitution located in the highly conserved amino-terminal domain of IHH. This domain is of importance for the interaction between IHH and the Patched receptor. Our combined findings add radiological findings to the BDA1 phenotype and confirm a critical functional domain of IHH.     

A novel mutation (A148V) in the glucose 6-phosphate translocase (SLC37A4) gene in a Korean patient with glycogen storage disease type 1b

We report a Korean patient with glycogen storage disease type 1b (GSD-1b) whose diagnosis was confirmed by liver biopsy and laboratory results. The patient presented with delay of puberty and short stature on admission and had typical clinical symptoms of GSD as well as chronic neutropenia and inflammatory bowel disease. Mutation analysis of the glucose 6-phosphate translocase 6-phosphate translocase (SLC37A4) gene revealed that the patient was a compound heterozygote of two different mutations including a deletion mutation (c.1042_1043delCT; L348fs) and a missense mutation (A148V). The L348fs mutation was inherited from the patient's father and has been reported in an Italian family with GSD-1b, while the A148V mutation was transmitted from the patient's mother and was a novel mutation. To the best of our knowledge, this is the first report of genetically confirmed case of GSD-1b in Korean.     

Exonic sequencing revealed no causative mutation in the BST1 gene in patients with Parkinson's disease

Genome-wide association and large-scale replication studies have linked Parkinson's disease (PD) to a locus on 4p15 encompassing a single gene encoding bone marrow stromal cell antigen 1 (BST1). To screen for causative mutations of BST1 in PD, we have directly sequenced all the 9 exons of BST1 in a Chinese cohort consisting of 524 PD cases and 527 controls. As a result, 6 known and 1 novel single-nucleotide polymorphisms (SNPs) were identified in exons 1, 3, 4, 7, and 9. However, none of these SNPs were associated with PD. The data, together with previous reports, suggested that the association between BST1 and PD might be determined by the noncoding sequences of the gene.     

Distribution of fibroblast growth factor receptor-1 (FGFR-1) and FGFR-3 in the hippocampus of patients with Alzheimer''s disease

To learn about the localization of fibroblast growth factor (FGF) ligands in normal and pathologic brains, fibroblast growth factor receptor-1 (FGFR-1; Flg) and FGFR-3 immunoreactivities were examined in the hippocampus of patients with Alzheimer's disease and age-matched controls. Flg immunoreactivity was found in practically all neurons of the hippocampus and dentate gyrus in control and Alzheimer's disease cases. In patients with Alzheimer's disease, Flg immunoreactivity was present in tangle-bearing and non-tangle-bearing neurons, as well as in neurons with granulovacuolar degeneration, but not in ghost tangles. Aberrant neurites of senile plaques were negative. FGFR-3 immunoreactivity was found in reactive glial cells, most of them astrocytes, including those in the vicinity of senile plaques.     

HEXIM1在先天性心脏病室间隔缺损中的突变及表达研究

目的通过筛查HEXIM1基因在室间隔缺损(ventricular septal defect,VSD)外周血中的突变和心肌组织中的表达情况,探讨HEXIM1基因与VSD发病机制的关系。方法采用PCR-DNA测序技术对100例单纯性室间隔缺损的患儿外周血进行基因编码序列突变筛查;以β-actin为内对照,用RT-PCR方法检测HEXIM1基因在14例室间隔缺损引产胎儿中mRNA的表达情况。结果所有研究对象的HEXIM1基因测序后同GenBank人类HEXIM1编码序列进行比较,有3例患儿(单纯性室间隔缺损)分别存在单核苷酸的多态性(SNP);与正常心肌组织相比,VSD引产胎儿心肌组织中HEXIM1基因mRNA表达呈下降趋势(P<0.05)。结论本实验收集的病例标本中没有发现HEXIM1基因编码区的突变,基因转录水平异常可能是该基因参与VSD形成的一种潜在机制。     

Identification of a novel mutation in the ATP7A gene in a Korean patient with Menkes disease

Menkes disease is an infantile-onset X-linked recessive neurodegenerative disorder caused by diverse mutations in a copper-transport gene, ATP7A. Affected patients are characterized by progressive hypotonia, seizures, failure to thrive and death in early childhood. Here, we report a case of Menkes disease presented by intractable seizures and infantile spasms. A 3-month-old male infant had visited our pediatric clinic for lethargy, floppy muscle tone, poor oral intake and partial seizures. His hair was kinky, brown colored and fragile. Partial seizures became more frequent, generalized and intractable to antiseizure medications. An EEG showed frequent posteriorly dominant generalized spikes that were consistent with a generalized seizure. From a genetic analysis, a c.2743C>T (p.Gln915X) mutation was detected and diagnosed as Menkes disease. The mutation is a novel one that has not been previously reported as a cause of Menkes disease.     

Novel missense mutation (Leu466Arg) of the DAX1 gene in a patient with X-linked congenital adrenal hypoplasia.

We identified a DAX1 missense mutation, a substitution of arginine for leucine at codon 466 (Leu466Arg), in an infant with X-linked congenital adrenal hypoplasia (AHC). A heterozygous substitution, Leu466Arg, was also identified in his mother and sister. Since leucine at position 466 is well conserved among other orphan nuclear hormone receptor superfamilies and Leu466Arg was not detected among 50 normal Japanese control individuals, the mutation is most likely responsible for X-linked AHC. It is interesting to note that Leu466Arg among all mutations ever reported is located at the most C-terminal region of the DAX-1 protein. Most mutations identified previously were located in the C-terminal presumptive ligand binding domain. Hence, the C-terminal end of the DAX-1 protein may play an important role in the biological function, such as in normal adrenal embryogenesis.     

NEFL Pro22Arg mutation in Charcot-Marie-Tooth disease type 1

Charcot-Marie-Tooth disease (CMT) is classified into demyelinating neuropathy (CMT1) and axonal neuropathy (CMT2). Mutations in the neurofilament light chain polypeptide (NEFL) gene are present in CMT2E and CMT1F neuropathies. Two types of Pro22 mutations have been previously reported: Pro22Ser in CMT2E with giant axons, and Pro22Thr in CMT1F. In this study, we identified another Pro22 mutation, Pro22Arg, in a Korean CMT1 family. An investigation to identify the clinical and pathological characteristics of the Pro22Arg revealed that it is associated with demyelinating neuropathy features in CMT1F. Histopathological findings showed onion bulb formations but no giant axons. It appears that the Pro22 mutations may influence not only the Thr-Pro phosphorylation site by proline-directed protein kinases but also other structural alteration of the NEFL protein in a different way. J.S. Shin and K.W. Chung contributed equally to this work.     

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) in two Mexican brothers harboring a novel mutation in the ECGF1 gene

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by mutations in the thymidine phosphorylase gene located on chromosome 22q13.32-ter, causing defective functioning of the enzyme. At present 87 sporadic or familial cases have been reported and 52 different mutations identified. We present herein the clinical, neuromuscular and molecular findings of two affected brothers from an indigenous Mexican family living in a very small village not far from Mexico City, both brothers being homozygous for a novel mutation (Leu133Pro) in exon 3 of the ECGF1 gene.