Neurotox Res DOI 10.1007/s12640-014-9462-3
ORIGINAL ARTICLE
Identification of a Novel Mutation in the Presenilin 1 Gene in a Chinese Alzheimer’s Disease Family Bo Deng • Yan Lian • Xin Wang • Fan Zeng • Bin Jiao • Ye-Ran Wang • Chun-Rong Liang • Yu-Hui Liu • Xian-Le Bu • Xiu-Qing Yao • Chi Zhu Lu Shen • Hua-Dong Zhou • Tao Zhang • Yan-Jiang Wang
•
Received: 8 January 2014 / Revised: 20 February 2014 / Accepted: 20 February 2014 Ó Springer Science+Business Media New York 2014
Abstract This study has identified a gene mutation in a Chinese family with Alzheimer’s disease (AD). Family members were screened by a set of medical examinations and neuropsychological tests. Their DNA was extracted from blood cells and sequenced for gene mutation in the amyloid precursor protein (APP), the presenilin 1 (PS1) and the presenilin 2 (PS2) genes. Genetic analysis showed that the AD patients in the family harbored a T to G missense mutation at the position 314 in exon 4 of the PS1 gene, resulting in a change of F105C in amino acid sequence. Clinical manifestation of these patients included memory loss, counting difficulty, personality change, disorientation, dyscalculia, agnosia, aphasia, and apraxia, which was similar to that of the familial AD (FAD) patients harboring other PS1 mutations. We intend to add a novel mutation F105C of the PS1 gene to the pool of FAD mutations. With the current available genetic data,
Bo Deng and Yan Lian have contributed equally to this work. B. Deng X. Wang F. Zeng Y.-R. Wang C.-R. Liang Y.-H. Liu X.-L. Bu X.-Q. Yao C. Zhu H.-D. Zhou T. Zhang (&) Y.-J. Wang (&) Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China e-mail: [email protected]
mutations of the PS1 gene account for the majority of gene mutations in Chinese FAD. Keywords Familial Alzheimer’s disease Presenilin 1 F105C mutation
Introduction Alzheimer’ disease (AD) is a common neurodegenerative disorder characterized by progressive memory deficit, visuospatial disorder, aphasia, agnosia, impairment of abstract thinking and calculation, and personality and behavior change. AD can be classified into sporadic AD and familial AD (FAD). The pathogenesis of AD remains unclear. Familiar AD, includes early-onset familial AD (EOFAD) and late-onset familial AD (LOFAD), accounts for less than 5 % of the total AD patients. EOFAD is an autosomal dominant AD which accounts for a large percentage of FAD and mainly owes to mutations in the amyloid precursor protein (APP) and the presenilin 1 (PS1) and the presenilin 2 (PS2) genes. Most of the mutations locate in the PS1 gene. To date, about 200 PS1 gene mutations have been identified in the population of western countries (Cruts et al. 2012). However, gene mutations in Chinese FAD remain unknown. Here, we report a Chinese FAD family, whose diseases are caused by a novel mutation in the PS1 gene.
Y.-J. Wang e-mail: [email protected] Y. Lian Department of Prevention Medicine, Daping Hospital, Third Military Medical University, Chongqing, China B. Jiao L. Shen Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
Materials and Methods Study Subjects The FAD family was found in Jiangjin district, Chongqing, China. Among the total 21 lineal familial members,
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Neurotox Res Fig. 1 Pedigree of the family. Arrow indicates the proband, black symbols denote affected members, white symbols denote unaffected members, gray symbols denote the possibly atrisk members, square denotes man, circle denotes women, (nn/nn) denotes age-at-onset/ current age or age-at-death, and (nn) denotes current age or ageat-death
one male and one female are affected with AD, and one was affected with dementia before his death. The proband (II 9) had ten siblings. Six siblings died when they were infants (less than 1 year old) and suffered no dementia before their deaths. Two sisters (II 6 and II 13) are alive and cognitively normal upon our examination. There is no available information on the ancestors of proband’s parents (Fig. 1). Clinical Assessment All the familial members were visited with their medical history collected from medical records and current medication. The data included prior head trauma and surgery, prior gas poisoning, schizophrenia, hypothyroidism, coronary heart disease, atrial fibrillation, cerebrovascular diseases defined by history, chronic obstructive pulmonary disease, chronic hepatitis, chronic renal insufficiency, hypertension, diabetes mellitus, hypercholesterolemia, Parkinson disease, and regular use of nonsteroidal antiinflammatory drugs. The familial members were screened for dementia with Chinese version of mini-mental state examination (MMSE) and Instrumental activities of daily living (ADL). Subjects with cognitive decline were further administered with a battery of neuropsychological tests used in our previous studies (Zeng et al. 2013; Li et al. 2011), including clinical dementia rating (CDR), Fuld Object Memory Evaluation for detecting extensive cognitive dysfunction mainly composed of memory, rapid verbal retrieve for detecting the function of semantic memory, Wechsler Adult Intelligence Scale (Digit Span and Block Design subtests) for evaluating immediate memory and function of graphical recognition, Hamilton Depression Rating Scale for measuring emotional status, and Hachinski Ischemic Score for evaluating significant vascular diseases. All the alive familial members in the second generation were subjected to brain imaging (CT or MRI) and blood tests for hemogram, fasting glucose, thyroxin, creatinine, uric acid, transaminase, total cholesterol, vitamin B12, and APOE genotypes.
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Diagnosis of Mild Cognitive Impairment (MCI) and AD The clinical diagnosis of MCI was made according to the established Petersen criteria (Petersen et al. 1999), including subjective complaint of memory deficits, abnormal memory functioning for age, absence of dementia according to the diagnostic examination (CDR \1), and normal everyday functioning on ADL. Clinical diagnosis of possible or probable AD was based on criteria of Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association. DNA Sequencing Blood were collected in the EDTA anticoagulant tube, and DNA was extracted with DNA Purification Kit (Wizard Genomic, Promega). All DNA samples were normalized to 50 ng/ll for polymerase chain reaction (PCR), which was performed on the exonic regions of PSEN1 (NM_000021.3; NP_000012.1), PSEN2 (NM_000447.2; NP_000438.2), and APP (NM_000484.3; NP_000475.1), as well as the corresponding flanking intronic sequences. PSEN1 (exons3–12), PSEN2 (exons3–12), and APP (exons16–17) were amplified using primers designed according to the Gene Bank entries and are available on request. Each PCR product was sequenced using the same forward and reverse primers with BigDye v3.1 sequencing chemistry and performed on an ABI 3730xl DNA analyzer (Applied Biosystems). The DNA sequences were analyzed with Sequencer software. To assess the likelihood that the novel mutation is pathogenic, we firstly used the SIFT online software to predict the novel variant’s pathogenicity. Direct sequencing was performed in the clinically affected and unaffected members of the family. The novel mutation was further verified in control individuals of matched geographical ancestry. This founding provides further evidence of the mutation’s pathogenicity.
Neurotox Res Fig. 2 Brain images of the familial members. Brain MRI of the proband (II 9) and brain CT images of the patient (II 11) showed brain atrophy in the frontotemporal regions, hippocampal areas (arrow), and lateral ventricle dilation, while the two cognitively normal sisters (II 6 and II 13) showed no obvious brain image abnormality
Results Clinical Manifestation of Familial Members Affected with AD The proband (II 9) was a 59-year-old female, whose memory loss and counting difficulty were presented at age of 45, and progressively worsen thereafter. She presented personality change at age of 50, and completely lost her ability of self-care at her 56. Neuropsychological tests revealed impaired memory, disorientation, dyscalculia, agnosia, aphasia, and apraxia. No focal neurological signs were found.
The patient 2 (II 11) was a 56-year-old male who presented memory decline at age of 51. He started to show personality change, disorientation, and needed help with self-care at age of 55. Neuropsychological and neurological examinations showed impaired memory without focal neurological signs. The patient 3 (I 1) died at age of 60. The family members recalled his manifestation of memory loss and hypologia at age of 50. He was diagnosed as dementia before his death. There was no detailed record for the diagnosis of specific type of dementia. Two sisters of the proband (II 6 and II 13) were at the age of 64 and 51 years, respectively; both of them showed
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Fig. 3 DNA sequencing of exon 4 of the PSEN1 gene in the family. a Familial members affected with AD carrying a T to G missense mutation at position 314 in exon 4 of the PS1 gene; b DNA sequence of exon 4 of the PS1 gene of unaffected familial members
no memory loss. Neurological and neuropsychological examination results of them were normal. The familial member II 1 died of some injury at 45, and the familial member II2-5 and II8 died in their early ages. All these people had no memory deficit before death. The third and fourth generations of the family were less than 50 years old and with no complaint of memory loss, and they were neurologically and psychologically normal. Brain Image Brain MRI or CT images of the proband (II 9) and the patient (II 11) showed brain atrophy in the frontotemporal regions, hippocampal areas, and lateral ventricle dilation, while two cognitively normal sisters showed no obvious abnormality in brain images (Fig. 2). Identification of Gene Mutation The two AD patients (II 9 and II 11) carried a missense mutation of T to G at position 314 in exon 4 of the PS1 gene, resulting in a Phe to Cys substitution at codon 105 (F105C), while the cognitively normal sisters (II 6 and II 13) did not harbor this mutation. The son (III 7) of the AD patient (II 11) did not harbor this mutation, and the son (III 5) of AD patients (II 9) declined the genetic examination. The SIFT online software showed F105C is ‘‘damaging’’. Moreover, this mutation was not found in other unaffected familial members or controls of matched geographical ancestry (Fig. 3).
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Discussion In the present study, we identified a novel mutation of F105C in exon 4 of the PS1 gene in a Chinese FAD family. Three amino acid mutations at this codon (F105L, F105I, and F105V) of the PS1 gene have been identified before (Cruts et al. 2012). Patients carrying the mutations at codon 105 have similar manifestation in the previous studies. Memory deficit is the main complaint in the early stage of the disease, which usually starts at age of 50 years or so. With the progress of the disease, some of the patients present Parkinson-like symptoms (Finckh et al. 2000; Gomez-Tortosa et al. 2010). The clinical manifestation of the patients carrying F105C mutation in the family is almost similar to that of patients harboring other mutations at codon 105 of the PS1 gene. However, our cases did not show Parkinson-like symptoms, the family members did not recall Parkinson-like symptoms on the proband’s father. The PS1 gene was cloned and named because of its association with AD in 1995 (Sherrington et al. 1995). About 200 mutations have been identified in the PS1 gene so far and most are pathogenic. PS1 protein is a component of gamma-secretase with 8 transmembrane domains and 467 residues (Dewji 2006). Mutations in the PS1 gene lead to an abnormal cleavage of APP by gamma-secretase (De Strooper et al. 1998), resulting in amyloid-beta 42 (Ab42) over-production and Ab accumulation in the brain. The codon 105 encodes the first hydrophilic loop domain, which is one of the functionally important regions of PS1 protein. Post-translational modification, spatial structure or
Neurotox Res
interaction with other proteins might be changed when mutations occur at this codon. Further studies are needed to address the pathogenic mechanism underlying the mutation. Clinical phenotype of AD caused by the PS1 gene mutations includes not only cognitive decline but also epileptic seizures, Parkinsonism, myoclonus, spastic paraparesis, cerebellar ataxia, and behavioral features suggestive of frontotemporal dementia (Larner 2013), while the manifestation caused by the PS2 gene mutations mainly includes Parkinsonism, seizures, and frontotemporal dementia-like phenotype. The clinical phenotype of AD caused by the APP gene mutations is relatively different from that caused by mutations in PS1 or PS2. Many patients carrying APP mutations share a history of repeated occurrence of cerebral hemorrhage because of the cerebral amyloid angiopathy. Seven Chinese FAD pedigrees have been reported so far, but two of them did not conduct DNA sequencing. Among the five Chinese FAD families with DNA sequencing data available, five different mutations were identified, including three mutations in the PS1 gene (S169del, V97L and A136G) (Guo et al. 2010; Jia et al. 2005; Xu et al. 2002) and two in the APP gene (V715M and D678H)(Lan et al. 2013; Nan et al. 2011). Moreover, these three PS1 gene mutations were mainly located at exon 4 and 5. To our knowledge, no mutation in the PS2 gene has been identified in Chinese FAD for so far. In this study, we added a novel mutation to the pool of gene mutations in FAD. Consistent with mutation distribution in population of western countries (Cruts et al. 2012), the PS1 gene also account for the majority of EOFAD in Chinese population. Further studies are needed to illustrate the pathogenesis of FAD caused by the F105C mutation identified in the present study. Acknowledgments This work was supported by the National Natural Science Foundation of China (Grant No. 81270423 and 30973144), the Natural Science Foundation Project of CQCSTC (Grant No. CSTC2010BA5004), China Postdoctoral Science Foundation (Grant No. 2012M521861), and the Chongqing Postdoctoral Science Foundation (Grant No. Xm201342). Ethical standards The study was approved by the Institutional Review Board of Daping Hospital. Written consents for genetic screening were obtained from all participants or their legal representatives. Conflict of interest
There are no conflicts of interest.
References Cruts M, Theuns J, Van Broeckhoven C (2012) Locus-specific mutation databases for neurodegenerative brain diseases. Hum Mutat 33(9):1340–1344. doi:10.1002/humu.22117
De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F (1998) Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391(6665):387–390. doi:10.1038/34910 Dewji NN (2006) Presenilin structure in mechanisms leading to Alzheimer’s disease. J Alzheimers Dis 10(2):277–290 Finckh U, Muller-Thomsen T, Mann U, Eggers C, Marksteiner J, Meins W, Binetti G, Alberici A, Hock C, Nitsch RM, Gal A (2000) High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet 66(1):110–117. doi:10.1086/ 302702 Gomez-Tortosa E, Barquero S, Baron M, Gil-Neciga E, Castellanos F, Zurdo M, Manzano S, Munoz DG, Jimenez-Huete A, Rabano A, Sainz MJ, Guerrero R, Gobernado I, Perez-Perez J, JimenezEscrig A (2010) Clinical-genetic correlations in familial Alzheimer’s disease caused by presenilin 1 mutations. J Alzheimer’s Dis 19(3):873–884. doi:10.3233/JAD-2010-1292 Guo J, Wei J, Liao S, Wang L, Jiang H, Tang B (2010) A novel presenilin 1 mutation (Ser169del) in a Chinese family with earlyonset Alzheimer’s disease. Neurosci Lett 468(1):34–37. doi:10. 1016/j.neulet.2009.10.055 Jia J, Xu E, Shao Y, Jia J, Sun Y, Li D (2005) One novel presenilin-1 gene mutation in a Chinese pedigree of familial Alzheimer’s disease. J Alzheimer’s Dis 7(2):119–124 discussion 173–180 Lan MY, Liu JS, Wu YS, Peng CH, Chang YY (2013) A novel APP mutation (D678H) in a Taiwanese patient exhibiting dementia and cerebral microvasculopathy. J Clin Neurosci. doi:10.1016/j. jocn.2013.03.038 Larner AJ (2013) Presenilin-1 mutations in Alzheimer’s disease: an update on genotype-phenotype relationships. J Alzheimer’s Dis 37(4):653–659. doi:10.3233/JAD-130746 Li J, Wang YJ, Zhang M, Xu ZQ, Gao CY, Fang CQ, Yan JC, Zhou HD, Chongqing Ageing Study G (2011) Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease. Neurology 76(17):1485–1491. doi:10.1212/WNL. 0b013e318217e7a4 Nan S, Han Y, Fan J, Chen Q (2011) Identification of a rare amyioid precursor protein gene mutation in a Chinese family with earlyonset familial alzheimer’s disease. Chin J Neuromed 44(1):47–51. doi:10.3760/cma.j.issn.1006-7876.2011.01.013 Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E (1999) Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 56(3):303–308 Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH (1995) Cloning of a gene bearing missense mutations in earlyonset familial Alzheimer’s disease. Nature 375(6534):754–760. doi:10.1038/375754a0 Xu E, Jia J, Sun W (2002) Mutation site of presenilin-1 gene in familial Alzheimer’s disease. Zhonghua yi xue za zhi 82(22):1518–1520 Zeng F, Zou HQ, Zhou HD, Li J, Wang L, Cao HY, Yi X, Wang X, Liang CR, Wang YR, Zhang AQ, Tan XL, Peng KR, Zhang LL, Gao CY, Xu ZQ, Wen AQ, Lian Y, Zhou XF, Wang YJ (2013) The relationship between single nucleotide polymorphisms of the NTRK2 gene and sporadic Alzheimer’s disease in the Chinese Han population. Neurosci Lett 550:55–59. doi:10.1016/ j.neulet.2013.06.061
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ORIGINAL ARTICLE
Identification of a Novel Mutation in the Presenilin 1 Gene in a Chinese Alzheimer’s Disease Family Bo Deng • Yan Lian • Xin Wang • Fan Zeng • Bin Jiao • Ye-Ran Wang • Chun-Rong Liang • Yu-Hui Liu • Xian-Le Bu • Xiu-Qing Yao • Chi Zhu Lu Shen • Hua-Dong Zhou • Tao Zhang • Yan-Jiang Wang
•
Received: 8 January 2014 / Revised: 20 February 2014 / Accepted: 20 February 2014 Ó Springer Science+Business Media New York 2014
Abstract This study has identified a gene mutation in a Chinese family with Alzheimer’s disease (AD). Family members were screened by a set of medical examinations and neuropsychological tests. Their DNA was extracted from blood cells and sequenced for gene mutation in the amyloid precursor protein (APP), the presenilin 1 (PS1) and the presenilin 2 (PS2) genes. Genetic analysis showed that the AD patients in the family harbored a T to G missense mutation at the position 314 in exon 4 of the PS1 gene, resulting in a change of F105C in amino acid sequence. Clinical manifestation of these patients included memory loss, counting difficulty, personality change, disorientation, dyscalculia, agnosia, aphasia, and apraxia, which was similar to that of the familial AD (FAD) patients harboring other PS1 mutations. We intend to add a novel mutation F105C of the PS1 gene to the pool of FAD mutations. With the current available genetic data,
Bo Deng and Yan Lian have contributed equally to this work. B. Deng X. Wang F. Zeng Y.-R. Wang C.-R. Liang Y.-H. Liu X.-L. Bu X.-Q. Yao C. Zhu H.-D. Zhou T. Zhang (&) Y.-J. Wang (&) Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China e-mail: [email protected]
mutations of the PS1 gene account for the majority of gene mutations in Chinese FAD. Keywords Familial Alzheimer’s disease Presenilin 1 F105C mutation
Introduction Alzheimer’ disease (AD) is a common neurodegenerative disorder characterized by progressive memory deficit, visuospatial disorder, aphasia, agnosia, impairment of abstract thinking and calculation, and personality and behavior change. AD can be classified into sporadic AD and familial AD (FAD). The pathogenesis of AD remains unclear. Familiar AD, includes early-onset familial AD (EOFAD) and late-onset familial AD (LOFAD), accounts for less than 5 % of the total AD patients. EOFAD is an autosomal dominant AD which accounts for a large percentage of FAD and mainly owes to mutations in the amyloid precursor protein (APP) and the presenilin 1 (PS1) and the presenilin 2 (PS2) genes. Most of the mutations locate in the PS1 gene. To date, about 200 PS1 gene mutations have been identified in the population of western countries (Cruts et al. 2012). However, gene mutations in Chinese FAD remain unknown. Here, we report a Chinese FAD family, whose diseases are caused by a novel mutation in the PS1 gene.
Y.-J. Wang e-mail: [email protected] Y. Lian Department of Prevention Medicine, Daping Hospital, Third Military Medical University, Chongqing, China B. Jiao L. Shen Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
Materials and Methods Study Subjects The FAD family was found in Jiangjin district, Chongqing, China. Among the total 21 lineal familial members,
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Neurotox Res Fig. 1 Pedigree of the family. Arrow indicates the proband, black symbols denote affected members, white symbols denote unaffected members, gray symbols denote the possibly atrisk members, square denotes man, circle denotes women, (nn/nn) denotes age-at-onset/ current age or age-at-death, and (nn) denotes current age or ageat-death
one male and one female are affected with AD, and one was affected with dementia before his death. The proband (II 9) had ten siblings. Six siblings died when they were infants (less than 1 year old) and suffered no dementia before their deaths. Two sisters (II 6 and II 13) are alive and cognitively normal upon our examination. There is no available information on the ancestors of proband’s parents (Fig. 1). Clinical Assessment All the familial members were visited with their medical history collected from medical records and current medication. The data included prior head trauma and surgery, prior gas poisoning, schizophrenia, hypothyroidism, coronary heart disease, atrial fibrillation, cerebrovascular diseases defined by history, chronic obstructive pulmonary disease, chronic hepatitis, chronic renal insufficiency, hypertension, diabetes mellitus, hypercholesterolemia, Parkinson disease, and regular use of nonsteroidal antiinflammatory drugs. The familial members were screened for dementia with Chinese version of mini-mental state examination (MMSE) and Instrumental activities of daily living (ADL). Subjects with cognitive decline were further administered with a battery of neuropsychological tests used in our previous studies (Zeng et al. 2013; Li et al. 2011), including clinical dementia rating (CDR), Fuld Object Memory Evaluation for detecting extensive cognitive dysfunction mainly composed of memory, rapid verbal retrieve for detecting the function of semantic memory, Wechsler Adult Intelligence Scale (Digit Span and Block Design subtests) for evaluating immediate memory and function of graphical recognition, Hamilton Depression Rating Scale for measuring emotional status, and Hachinski Ischemic Score for evaluating significant vascular diseases. All the alive familial members in the second generation were subjected to brain imaging (CT or MRI) and blood tests for hemogram, fasting glucose, thyroxin, creatinine, uric acid, transaminase, total cholesterol, vitamin B12, and APOE genotypes.
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Diagnosis of Mild Cognitive Impairment (MCI) and AD The clinical diagnosis of MCI was made according to the established Petersen criteria (Petersen et al. 1999), including subjective complaint of memory deficits, abnormal memory functioning for age, absence of dementia according to the diagnostic examination (CDR \1), and normal everyday functioning on ADL. Clinical diagnosis of possible or probable AD was based on criteria of Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association. DNA Sequencing Blood were collected in the EDTA anticoagulant tube, and DNA was extracted with DNA Purification Kit (Wizard Genomic, Promega). All DNA samples were normalized to 50 ng/ll for polymerase chain reaction (PCR), which was performed on the exonic regions of PSEN1 (NM_000021.3; NP_000012.1), PSEN2 (NM_000447.2; NP_000438.2), and APP (NM_000484.3; NP_000475.1), as well as the corresponding flanking intronic sequences. PSEN1 (exons3–12), PSEN2 (exons3–12), and APP (exons16–17) were amplified using primers designed according to the Gene Bank entries and are available on request. Each PCR product was sequenced using the same forward and reverse primers with BigDye v3.1 sequencing chemistry and performed on an ABI 3730xl DNA analyzer (Applied Biosystems). The DNA sequences were analyzed with Sequencer software. To assess the likelihood that the novel mutation is pathogenic, we firstly used the SIFT online software to predict the novel variant’s pathogenicity. Direct sequencing was performed in the clinically affected and unaffected members of the family. The novel mutation was further verified in control individuals of matched geographical ancestry. This founding provides further evidence of the mutation’s pathogenicity.
Neurotox Res Fig. 2 Brain images of the familial members. Brain MRI of the proband (II 9) and brain CT images of the patient (II 11) showed brain atrophy in the frontotemporal regions, hippocampal areas (arrow), and lateral ventricle dilation, while the two cognitively normal sisters (II 6 and II 13) showed no obvious brain image abnormality
Results Clinical Manifestation of Familial Members Affected with AD The proband (II 9) was a 59-year-old female, whose memory loss and counting difficulty were presented at age of 45, and progressively worsen thereafter. She presented personality change at age of 50, and completely lost her ability of self-care at her 56. Neuropsychological tests revealed impaired memory, disorientation, dyscalculia, agnosia, aphasia, and apraxia. No focal neurological signs were found.
The patient 2 (II 11) was a 56-year-old male who presented memory decline at age of 51. He started to show personality change, disorientation, and needed help with self-care at age of 55. Neuropsychological and neurological examinations showed impaired memory without focal neurological signs. The patient 3 (I 1) died at age of 60. The family members recalled his manifestation of memory loss and hypologia at age of 50. He was diagnosed as dementia before his death. There was no detailed record for the diagnosis of specific type of dementia. Two sisters of the proband (II 6 and II 13) were at the age of 64 and 51 years, respectively; both of them showed
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Neurotox Res
Fig. 3 DNA sequencing of exon 4 of the PSEN1 gene in the family. a Familial members affected with AD carrying a T to G missense mutation at position 314 in exon 4 of the PS1 gene; b DNA sequence of exon 4 of the PS1 gene of unaffected familial members
no memory loss. Neurological and neuropsychological examination results of them were normal. The familial member II 1 died of some injury at 45, and the familial member II2-5 and II8 died in their early ages. All these people had no memory deficit before death. The third and fourth generations of the family were less than 50 years old and with no complaint of memory loss, and they were neurologically and psychologically normal. Brain Image Brain MRI or CT images of the proband (II 9) and the patient (II 11) showed brain atrophy in the frontotemporal regions, hippocampal areas, and lateral ventricle dilation, while two cognitively normal sisters showed no obvious abnormality in brain images (Fig. 2). Identification of Gene Mutation The two AD patients (II 9 and II 11) carried a missense mutation of T to G at position 314 in exon 4 of the PS1 gene, resulting in a Phe to Cys substitution at codon 105 (F105C), while the cognitively normal sisters (II 6 and II 13) did not harbor this mutation. The son (III 7) of the AD patient (II 11) did not harbor this mutation, and the son (III 5) of AD patients (II 9) declined the genetic examination. The SIFT online software showed F105C is ‘‘damaging’’. Moreover, this mutation was not found in other unaffected familial members or controls of matched geographical ancestry (Fig. 3).
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Discussion In the present study, we identified a novel mutation of F105C in exon 4 of the PS1 gene in a Chinese FAD family. Three amino acid mutations at this codon (F105L, F105I, and F105V) of the PS1 gene have been identified before (Cruts et al. 2012). Patients carrying the mutations at codon 105 have similar manifestation in the previous studies. Memory deficit is the main complaint in the early stage of the disease, which usually starts at age of 50 years or so. With the progress of the disease, some of the patients present Parkinson-like symptoms (Finckh et al. 2000; Gomez-Tortosa et al. 2010). The clinical manifestation of the patients carrying F105C mutation in the family is almost similar to that of patients harboring other mutations at codon 105 of the PS1 gene. However, our cases did not show Parkinson-like symptoms, the family members did not recall Parkinson-like symptoms on the proband’s father. The PS1 gene was cloned and named because of its association with AD in 1995 (Sherrington et al. 1995). About 200 mutations have been identified in the PS1 gene so far and most are pathogenic. PS1 protein is a component of gamma-secretase with 8 transmembrane domains and 467 residues (Dewji 2006). Mutations in the PS1 gene lead to an abnormal cleavage of APP by gamma-secretase (De Strooper et al. 1998), resulting in amyloid-beta 42 (Ab42) over-production and Ab accumulation in the brain. The codon 105 encodes the first hydrophilic loop domain, which is one of the functionally important regions of PS1 protein. Post-translational modification, spatial structure or
Neurotox Res
interaction with other proteins might be changed when mutations occur at this codon. Further studies are needed to address the pathogenic mechanism underlying the mutation. Clinical phenotype of AD caused by the PS1 gene mutations includes not only cognitive decline but also epileptic seizures, Parkinsonism, myoclonus, spastic paraparesis, cerebellar ataxia, and behavioral features suggestive of frontotemporal dementia (Larner 2013), while the manifestation caused by the PS2 gene mutations mainly includes Parkinsonism, seizures, and frontotemporal dementia-like phenotype. The clinical phenotype of AD caused by the APP gene mutations is relatively different from that caused by mutations in PS1 or PS2. Many patients carrying APP mutations share a history of repeated occurrence of cerebral hemorrhage because of the cerebral amyloid angiopathy. Seven Chinese FAD pedigrees have been reported so far, but two of them did not conduct DNA sequencing. Among the five Chinese FAD families with DNA sequencing data available, five different mutations were identified, including three mutations in the PS1 gene (S169del, V97L and A136G) (Guo et al. 2010; Jia et al. 2005; Xu et al. 2002) and two in the APP gene (V715M and D678H)(Lan et al. 2013; Nan et al. 2011). Moreover, these three PS1 gene mutations were mainly located at exon 4 and 5. To our knowledge, no mutation in the PS2 gene has been identified in Chinese FAD for so far. In this study, we added a novel mutation to the pool of gene mutations in FAD. Consistent with mutation distribution in population of western countries (Cruts et al. 2012), the PS1 gene also account for the majority of EOFAD in Chinese population. Further studies are needed to illustrate the pathogenesis of FAD caused by the F105C mutation identified in the present study. Acknowledgments This work was supported by the National Natural Science Foundation of China (Grant No. 81270423 and 30973144), the Natural Science Foundation Project of CQCSTC (Grant No. CSTC2010BA5004), China Postdoctoral Science Foundation (Grant No. 2012M521861), and the Chongqing Postdoctoral Science Foundation (Grant No. Xm201342). Ethical standards The study was approved by the Institutional Review Board of Daping Hospital. Written consents for genetic screening were obtained from all participants or their legal representatives. Conflict of interest
There are no conflicts of interest.
References Cruts M, Theuns J, Van Broeckhoven C (2012) Locus-specific mutation databases for neurodegenerative brain diseases. Hum Mutat 33(9):1340–1344. doi:10.1002/humu.22117
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