Systematic genetic study of Alzheimer disease in Latin America: Mutation frequencies of the amyloid β precursor protein and presenilin genes in Colombia*

Nearly all mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid β precursor protein (APP) genes lead to early‐onset Alzheimer disease (EOAD, onset age at or before 65 years). In order to assess the genetic contribution of these genes in a series of Colombian AD cases, we performed a systematic mutation analysis in 11 autosomal dominant, 23 familial, and 42 sporadic AD patients (34% with age of onset ≤ 65 years). No APP missense mutations were identified. In three autosomal dominant cases (27.2%), two different PSEN1 missense mutations were identified. Both PSEN1 mutations are missense mutations that occurred in early‐onset autosomal AD cases: an I143T mutation in one case (onset age 30 years) and an E280A mutation in two other cases (onset ages 35 and 42 years). In addition, a novel PSEN1 V94M mutation was present in one early‐onset AD case without known family history (onset age 53 years) and absent in 53 controls. The E318G polymorphism was present in five AD cases and absent in controls. In PSEN2, two different silent mutations were detected, including one not reported elsewhere (P129). The majority of the Colombian AD cases, predominantly late‐onset, were negative for PSEN and APP mutations. © 2001 Wiley‐Liss, Inc.     

Molecular diagnosis of autosomal dominant early onset Alzheimer's disease: an update

Background: Autosomal dominant early onset Alzheimer''s disease (ADEOAD) is genetically heterogeneous. Mutations of the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes have been identified. Objective: To further clarify the respective contribution of these genes to ADEOAD. Methods: 31 novel families were investigated. They were ascertained using stringent criteria (the occurrence of probable or definite cases of Alzheimer''s disease with onset before 60 years of age in three generations). All cases fulfilled the NINCDS-ADRDA criteria for probable or definite Alzheimer''s disease. The entire coding regions of PSEN1 and PSEN2 genes and exons 16 and 17 of APP gene were sequenced from genomic DNA Results: PSEN1 mutations, including eight previously unreported mutations, were detected in 24 of the 31 families, and APP mutations were found in five families. In this sample, the mean ages of disease onset in PSEN1 and APP mutation carriers were 41.7 and 51.2 years, respectively. Conclusions: Combining these data with previously published data, yielding 65 ADEOAD families, 66% of the cases were attributable to PSEN1 mutations and 16% to APP mutations, while 18% remained unexplained.     

Systematic genetic study of Alzheimer disease in Latin America: mutation frequencies of the amyloid beta precursor protein and presenilin genes in Colombia

Nearly all mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid beta precursor protein (APP) genes lead to early-onset Alzheimer disease (EOAD, onset age at or before 65 years). In order to assess the genetic contribution of these genes in a series of Colombian AD cases, we performed a systematic mutation analysis in 11 autosomal dominant, 23 familial, and 42 sporadic AD patients (34% with age of onset < or = 65 years). No APP missense mutations were identified. In three autosomal dominant cases (27.2%), two different PSEN1 missense mutations were identified. Both PSEN1 mutations are missense mutations that occurred in early-onset autosomal AD cases: an I143T mutation in one case (onset age 30 years) and an E280A mutation in two other cases (onset ages 35 and 42 years). In addition, a novel PSEN1 V94M mutation was present in one early-onset AD case without known family history (onset age 53 years) and absent in 53 controls. The E318G polymorphism was present in five AD cases and absent in controls. In PSEN2, two different silent mutations were detected, including one not reported elsewhere (P129). The majority of the Colombian AD cases, predominantly late-onset, were negative for PSEN and APP mutations.     

LOXL3 novel mutation causing a rare form of autosomal recessive Stickler syndrome

Stickler syndrome is a collagenopathy that is typically inherited as autosomal dominant disease caused by monoallelic mutations in COL2A1, COL11A2, and COL11A1. Rarely, biallelic mutations in COL9A1, COL9A2, and COL9A3 cause an autosomal recessive Stickler syndrome. One previous report described two siblings with Stickler syndrome and a homozygous mutation in LOXL3, suggesting that biallelic mutations in LOXL3 can also cause autosomal recessive Stickler syndrome. LOXL3 is a member of the lysyl oxidase family of genes which encode enzymes oxidizing the side chain of peptidyl lysine permitting the covalent crosslinking of collagen and elastin chains. Therefore, LOXL3 deficiency is expected to result in collagen defect. Furthermore, Loxl3 deficient mouse model demonstrated features overlapping with Stickler syndrome. In this report, we describe a child and his father who had clinical features consistent with Stickler syndrome and found to have a homozygous novel mutation c.1036C>T (p.Arg346Trp) in LOXL3. This report not only supports that biallelic LOXL3 mutations cause autosomal recessive Stickler syndrome, but also further delineates the phenotype associated with LOXL3 mutations. In addition, the family described here shows an interesting example for pseudodominance, which can be observed in recessive diseases when one parent is affected and the other is heterozygous carrier.     

Mutational analysis in early-onset familial Alzheimer's disease in Mainland China

Mutations of 3 causative genes, namely presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP), have been identified as the major causes of early-onset familial Alzheimer's disease (EOFAD). Recently, a GGGGCC repeat expansion in the noncoding region of C9orf72 was also detected in some patients with clinically diagnosed familial Alzheimer's disease. The prevalence of causative gene mutations in patients with EOFAD has been reported in previous studies but their prevalence remains unclear in Mainland China. The aim of this study was to characterize the common causative gene mutation spectrum and genotype-phenotype correlations in Chinese patients with EOFAD. Genetic screening for mutations in PSEN1, PSEN2, and APP was conducted in a total of 32 families with clinical diagnoses of EOFAD from Mainland China. Subsequently, a hexanucleotide repeat expansion in C9orf72 was detected in all patients. Four novel mutations in PSEN1 (p.A434T, p.I167del, p.F105C, and p.L248P) were identified in 4 respective families, and 1 previously recognized pathogenic mutation in APP (p.V717I) was detected in another 2 unrelated families. The PSEN2 mutation and pathogenic repeat expansions of C9orf72 were not detected in all patients. To the best of our knowledge, this is the first cohort report of a causative gene screen in patients with EOFAD in Mainland China. The analysis of the genetic-clinical correlations in this cohort supports the idea that the clinical phenotype might be influenced by specific genetic defects.     

Genetics of Wilson disease and Wilson-like phenotype in a clinical series from eastern Spain

Wilson's disease (WD) is an autosomal recessive disorder caused by ATP7B mutations. Subjects with only one mutation may show clinical signs and individuals with biallelic changes may remain asymptomatic. We aimed to achieve a conclusive genetic diagnosis for 34 patients clinically diagnosed of WD. Genetic analysis comprised from analysis of exons to WES (whole exome sequencing), including promoter, introns, UTRs (untranslated regions), besides of study of large deletions/duplications by MLPA (multiplex ligation-dependent probe amplification). Biallelic ATP7B mutations were identified in 30 patients, so that four patients were analyzed using WES. Two affected siblings resulted to be compound heterozygous for mutations in CCDC115, which is involved in a form of congenital disorder of glycosylation. In sum, the majority of patients with a WD phenotype carry ATP7B mutations. However, if genetic diagnosis is not achieved, additional genes should be considered because other disorders may mimic WD.     

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.     

Autosomal recessive Treacher Collins syndrome due to POLR1C mutations: Report of a new family and review of the literature

Treacher Collins syndrome (TCS) is a frequent cause of mandibulofacial dysostosis. To date, TCS‐causing mutations in three genes, namely TCOF1, POLR1D, and POLR1C have been identified. TCS is usually inherited in an autosomal dominant manner, with a high clinical variability and no phenotype–genotype correlation. Up‐to now, five families have been reported with an autosomal recessive mode of inheritance due to mutations in POLR1D or POLR1C. We report here a new family with two sisters affected by mild TCS carrying compound POLR1C heterozygous mutations, and review the literature on mild forms of TCS, autosomal recessive inheritance in this syndrome and POLR1C mutations.     

Mutations of the presenilin I gene in families with early-onset Alzheimer's disease

We analyzed 12 families with autosomal dominant early-onsetAlzheimer's disease (EOAD) for mutations in the coding regionof the presenilin I (PSNLI) gene corresponding to the AD3 locuson chromosome 14q24.3. A total of eight missense mutations atcodons 82, 115, 139, 163, 231, 264, 392, and 410, includingsix novel mutations, were identified in eight families. Cosegregationof the mutations with EOAD was confirmed in three families,one including 36 affected individuals. This study underlinesthe great allelic heterogeneity and the large distribution ofthe mutations within the PSNLI coding region. Our results supportthe notion that PSNLI is the major gene involved in autosomaldominant EOAD.     

Detecting gene mutations in Japanese Alzheimer's patients by semiconductor sequencing

Alzheimer's disease (AD) is the most common form of dementia. To date, several genes have been identified as the cause of AD, including PSEN1, PSEN2, and APP. The association between APOE and late-onset AD has also been reported. We here used a bench top next-generation sequencer, which uses an integrated semiconductor device, detects hydrogen ions, and operates at a high-speed using nonoptical technology. We examined 45 Japanese AD patients with positive family histories, and 29 sporadic patients with early onset (<60-year-old). Causative mutations were detected in 5 patients in the familial group (11%). Three patients had a known heterozygous missense mutation in the PSEN1 gene (p.H163R). Two patients from 1 family had a novel heterozygous missense mutation in the PSEN1 gene (p.F386L). In the early onset group, 1 patient carrying homozygous APOEε4 had a novel heterozygous missense mutation in the PSEN2 gene (p.T421M). Approximately 43% patients were APOEε4 positive in our study. This new sequencing technology is useful for detecting genetic variations in familial AD.     

Nonaka myopathy is caused by mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE)

This is the first report on mutations of the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE) in Nonaka myopathy or distal myopathy with rimmed vacuoles (OMIM 605820), an autosomal recessive neuromuscular disorder. Sequence and haplotype analyses of GNE in two siblings with Nonaka myopathy from a Japanese family revealed that both patients were compound heterozygotes for a C→T transition (A460V) in exon 8 and a G→C transition (V572L) in exon 10. Their parents and a normal elder brother were all carriers for one or the other of the mutations. GNE mutations are known to cause two other disorders: sialuria (OMIM #269921) and autosomal recessive inclusion body myopathy (IBM2, OMIM #600737). Mutations associated with sialuria are located in the epimerase domain, and those associated with IBM2 are in the epimerase or the kinase domain or both, whereas the mutations we observed in the Nonaka myopathy patients were located in the sugar kinase domain of the gene. Thus, Nonaka myopathy is the third disease known to be caused by GNE mutations. Received: October 12, 2001 / Accepted: November 9, 2001     

Homozygous deletion of RAG1, RAG2 and 5′ region TRAF6 causes severe immune suppression and atypical osteopetrosis

Mutations of several genes have been implicated in autosomal recessive osteopetrosis (OP), a disease caused by impaired function and differentiation of osteoclasts. Severe combined immune deficiencies (SCID) can likewise result from different genetic mutations. We report two siblings with SCID and an atypical phenotype of OP. A biallelic microdeletion encompassing the 5′ region of TRAF6, RAG1 and RAG2 genes was identified. TRAF6, a tumor necrosis factor receptor‐associated family member, plays an important role in T cell signaling and in RANKL‐dependent osteoclast differentiation and activation but its role in human OP has not been previously reported. The RAG proteins are essential for recombination of B and T cell receptors, and for the survival and differentiation of these cells. This is the first study to report a homozygous deletion of TRAF6 as a cause of human disease.     

Sclerosteosis caused by a novel nonsense mutation of SOST in a consanguineous family

Sclerosteosis, characterized by the hyperostosis of cranial and tubular bones, is a rare autosomal recessive hereditary disorder caused by mutation of SOST gene. Four nonsense mutations of SOST have been identified worldwide. Here, we report two affected siblings who carried a novel nonsense mutation of SOST in a consanguineous family from China. The proband manifested typical symptoms of sclerosteosis, whereas the symptoms were absent in another affected sibling. Two nucleotide substitutions in exon 2 of SOST were identified, c.444_445TC>AA, resulting in a premature stop codon, p.Cys148→Stop. This truncated mutation loses 66 amino acid residues which contain 3 cysteine residues of the cysteine‐knot motif, leading to loss of function of SOST. The symptoms of sclerosteosis may be clinically heterogeneous in some patients, even with the same mutation. Our results support the notion that founder effects from the ancestors contribute to the disease onset.     

X‐linked mental retardation with alacrima and achalasia—Triple A syndrome or a new syndrome?

We describe a consanguineous Israeli Arab kindred with five males in two interrelated families with intellectual disabilities, alacrima, achalasia, and mild autonomic dysfunction. Adrenal function is normal. Their phenotype is similar to the phenotype observed in autosomal recessive Triple A syndrome except for the presence of mental retardation in all affected individuals. The pedigree is compatible with either X‐linked or autosomal recessive inheritance. Sequencing of the AAAS gene causing autosomal recessive Triple A syndrome did not reveal mutations. Genotyping of affected family members identified a 16.4 Mb continuous segment of identical alleles shared by the patients between markers rs2748314 and rs5906782 on Xp11.23‐p21, establishing linkage to chromosome X. This study further confirms genetic heterogeneity in Triple A syndrome and points to a clinically different subtype including significant cognitive impairment. © 2011 Wiley‐Liss, Inc.     

A thorough assessment of benign genetic variability in GRN and MAPT

Mutations in APP, PSEN1, MAPTand GRNare the most common genetic causes of dementia. The previous miss‐assignment of pathogenicity to benign variants in these genes stresses the importance of discerning between disease causing mutations and benign variants with no pathogenic effect on the function of the respective protein. In this study we sequenced GRNand MAPTin 282 samples from the Centre d'Etude du Polymorphisme Humain ‐ Human Genome Diversity Cell Line Panel, in order to identify benign variants that could otherwise be mistaken for pathogenic mutations. We found sixteen different non‐synonymous changes, eleven of which are novel variants. © 2009 Wiley‐Liss, Inc.     

Strømme Syndrome Is a Ciliary Disorder Caused by Mutations in CENPF

Strømme syndrome was first described by Strømme et al. (1993) in siblings presenting with “apple peel” type intestinal atresia, ocular anomalies and microcephaly. The etiology remains unknown to date. We describe the long‐term clinical follow‐up data for the original pair of siblings as well as two previously unreported siblings with a severe phenotype overlapping that of the Strømme syndrome including fetal autopsy results. Using family‐based whole‐exome sequencing, we identified truncating mutations in the centrosome gene CENPF in the two nonconsanguineous Caucasian sibling pairs. Compound heterozygous inheritance was confirmed in both families. Recently, mutations in this gene were shown to cause a fetal lethal phenotype, the phenotype and functional data being compatible with a human ciliopathy [Waters et al., 2015 ]. We show for the first time that Strømme syndrome is an autosomal‐recessive disease caused by mutations in CENPF that can result in a wide phenotypic spectrum.