Identification of PSEN1 mutations p.M233L and p.R352C in Han Chinese families with early-onset familial Alzheimer's disease

doi:10.1016/j.neurobiolaging.2014.11.009

Neurobiology of Aging

Volume 36, Issue 3, March 2015, Pages 1602.e3-1602.e6

https://doi.org/10.1016/j.neurobiolaging.2014.11.009 Get rights and content

Abstract

Early-onset familial Alzheimer's disease (EOFAD) is characterized by the onset of dementia symptoms before 65 years, positive family history, high genetic predisposition, and an autosomal dominant inheritance. We aimed to investigate mutations and to characterize phenotypes in Chinese EOFAD families. Detailed clinical assessments and genetic screening for mutations in the presenilin 1 (PSEN1), presenilin 2, amyloid precursor protein, and APOE genes were carried out in 4 EOFAD families. Two PSEN1 mutations (p.R352C and p.M233L) were identified in 2 EOFAD families, respectively. Mutation p.M233L was associated with prominent very early onset, rapidly progressive dementia, and neurologic symptoms, whereas p.R352C was associated with a progressive dementia, psychiatric syndrome, and chronic disease course. Both mutations are predicted to be pathogenic. Our results showed that mutations in PSEN1 gene might be common in Chinese EOFAD families.

Introduction

Early-onset familial Alzheimer's disease (EOFAD) is characterized by the onset of progressive dementia symptoms before 65 years, positive family history, and more aggressive course than late-onset sporadic AD. To date, more than 230 mutations have been identified in the amyloid precursor protein (APP), the presenilin 1 (PSEN1), and the presenilin 2 (PSEN2) genes (Bettens et al., 2010, Wu et al., 2012).

Hitherto, there are a few reports about the PSEN1, PSEN2, and APP gene mutations in Han Chinese families (Jiao et al., 2014, Niu et al., 2014, Peng et al., 2014). Further mutation profiling is needed. In this study, we screened mutations of the 3 AD causal genes in 4 Han Chinese EOAD families. Two PSEN1 mutations (p.M233L and p.R352C) were identified in 2 of the 4 EOAD families. According to searches with available genetic database, p.R352C is a previously unidentified PSEN1 mutation, and p.M233L has been reported in European patients. The 2 mutations are associated with cognitive impairment and quite different clinical spectrum.

Section snippets

Methods

This study enrolled 4 Han Chinese EOFAD families. Five patients with progressive memory loss and 7 individuals without obvious cognitive dysfunction disorder from these 4 families were clinically evaluated by Mini-Mental State Examination and Montreal Cognitive Assessment (MoCA). All patients and unaffected individuals were recruited from the outpatient psychiatry department of the First Affiliated Hospital of Kunming Medical University, Yunnan Province. Magnetic resonance image scan and blood

Results

We evaluate the clinical phenotype and the clinical assessments score for partial individuals of the 4 families (Table 1). Brain magnetic resonance image of the probands from the 4 families showed generalized-global cerebral atrophy (Supplementary Fig. 2).

Two missense mutation of PSEN1 (p.R352C and p.M233L) and a homozygous APOE ε4 were respectively identified in 3 of the 4 EOAD families. No mutation of PSEN2 and APP was detected in these families (Table 1 and Fig. 1). Mutation p.M223L in exon

Discussion

PSEN1 is one of the most common and important causative gene of EOFAD, with more than 185 mutations being reported. Mutation p.M233L (c.697A>C, dbSNP ID: rs63751287) of PSEN1 was previously described in patients with AD (Aldudo et al., 1999, Rogaeva et al., 2001), whereas p.R352C was identified for the first time. Mutation p.M233L was associated with prominent very early onset, rapidly progressive dementia, and neurologic symptoms, whereas p.R352C was associated with a progressive dementia,

Conclusion

In short, we reported 4 Chinese EOFAD families and detected 2 missense PSEN1 mutations (p.R352C and p.M233L). The 2 mutations are predicted to be pathogenic. The phenotype of the 2 EOFAD carrying mutation is variable. Future studies are needed to explore the pathogenesis of p.R352C and p.M233L mutations in PSEN1, which may illuminate the underpinnings of Alzheimer's disease.

Disclosure statement

The authors have no conflicts of interest to disclose.

Acknowledgements

This study was supported by the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB02020300 to Yong-Gang Yao) and the National Program for Support of Top-notch Young Professionals (to Li Yu). The authors thank the individuals who participated in this study.

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¹: These authors contributed equally to this work.

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Genetic report abstractBrief communicationIdentification of PSEN1 mutations p.M233L and p.R352C in Han Chinese families with early-onset familial Alzheimer's disease

Abstract

Introduction

Section snippets

Methods

Results

Discussion

Conclusion

Disclosure statement

Acknowledgements

Neurobiol. Dis.

Neurobiol. Aging

Am. J. Hum. Genet.

Neurobiol. Aging

Neurosci. Lett.

Neurobiol. Aging

Neurobiol. Aging

Neurobiol. Aging

Genetic report abstract
Brief communication
Identification of PSEN1 mutations p.M233L and p.R352C in Han Chinese families with early-onset familial Alzheimer's disease