**2.1 Sporadic PD and** *SNCA* **duplication**

In 2007, Ahn et al reported two sporadic patients with *SNCA* duplication from a screen of 906 PD patients (Ahn et al., 2008). The age at onset was 65 and 50 years old for the two patients. Their clinical course was similar to typical sporadic PD without severe progression or cognitive decline. The estimated penetrance ratio was 33.3% among the Korean patients. Our studies have also detected one sporadic patient with *SNCA* duplication and this means that the low penetrance *SNCA* duplications may give the appearance of sporadic disease.

### **2.2 The frequency of** *SNCA* **multiplications in PD**

The prevalence of *SNCA* multiplications is relatively low (table 1). Bruggemann et al reported one sporadic case among 403 PD cases from Germany (1/403=0.25%) (Brueggemann et al., 2008). Troiano et al reported one sporadic cases among 101 young onset PD cases from French (1/101=1%) (Troiano et al., 2008). Nuytemans et al reported one duplication patient with dementia among 219 sporadic PD cases from Belgium (Nuytemans et al., 2009). Sironi et al reported one duplication patient with dementia among 144 PD cases from Italy (1/144=0.7%) (Sironi et al., 2009). Furthermore some reports did not detect *SNCA* duplication; 0/50 and 0/290 (Hope et al., 2004, Xiromerisiou et al., 2007). To conclude, *SNCA* multiplication is not a common cause of sporadic or hereditary PD.

### **2.3** *SNCA* **multiplications in multiple system atrophy**

Multiple system atrophy (MSA) is characterized by specific clinical features such as Parkinsonism, autonomic dysfunction, poor response to levodopa therapy, and cerebellar ataxia (Wenning et al., 2004). Glial cytoplasmic inclusions (GCIs) are the pathologic hallmark of the disease. As alpha-synuclein is a major protein component of GCIs, MSA is categorized within the group of neurodegenerative disorders classified as the alphasynucleinopathies. Interestingly common variation at the *SNCA* locus has been associated with MSA risk (Scholz et al., 2009, Ross et al., 2010). Two studies did not identify any *SNCA* multiplications in a combined total of 258 MSA patients (Lincoln et al., 2007, Ahn et al., 2008). Although the number of assessed samples may be small, these findings suggest that *SNCA* dosage is not a common cause of MSA. It is speculated that PD or DLB may be cause by lysosomal dysfunction, however, MSA may be caused by the oligodendrocytic changes in myelin basic protein (Wenning et al., 2008).

Swedish family named the "Lister family complex" has both *SNCA* duplication and triplication patients within different branches of the pedigree suggesting a primary duplication event followed later by another resulting in the triplication (Fuchs et al., 2007). In this family also the patient with *SNCA* triplication presented with more severe symptoms than the patients with duplication. Recently one small pedigree with SNCA triplication was

The breakpoint of *SNCA* multiplication is different in each family. The largest multiplication about 4.9Mb is detected within a French family. The smallest one about 0.2 Mb is in a Japanese family (Nishioka et al., 2009). The size and gene make-up of each multiplication region does not seem to influence the clinical presentation of the carrier. The single common determining factor that appears between all patients with *SNCA* multiplication is the presence of the entire *SNCA* gene. To conclude, it is clear that *SNCA* multiplication alone is

In 2007, Ahn et al reported two sporadic patients with *SNCA* duplication from a screen of 906 PD patients (Ahn et al., 2008). The age at onset was 65 and 50 years old for the two patients. Their clinical course was similar to typical sporadic PD without severe progression or cognitive decline. The estimated penetrance ratio was 33.3% among the Korean patients. Our studies have also detected one sporadic patient with *SNCA* duplication and this means that the low penetrance *SNCA* duplications may give the appearance of sporadic disease.

The prevalence of *SNCA* multiplications is relatively low (table 1). Bruggemann et al reported one sporadic case among 403 PD cases from Germany (1/403=0.25%) (Brueggemann et al., 2008). Troiano et al reported one sporadic cases among 101 young onset PD cases from French (1/101=1%) (Troiano et al., 2008). Nuytemans et al reported one duplication patient with dementia among 219 sporadic PD cases from Belgium (Nuytemans et al., 2009). Sironi et al reported one duplication patient with dementia among 144 PD cases from Italy (1/144=0.7%) (Sironi et al., 2009). Furthermore some reports did not detect *SNCA* duplication; 0/50 and 0/290 (Hope et al., 2004, Xiromerisiou et al., 2007). To conclude,

Multiple system atrophy (MSA) is characterized by specific clinical features such as Parkinsonism, autonomic dysfunction, poor response to levodopa therapy, and cerebellar ataxia (Wenning et al., 2004). Glial cytoplasmic inclusions (GCIs) are the pathologic hallmark of the disease. As alpha-synuclein is a major protein component of GCIs, MSA is categorized within the group of neurodegenerative disorders classified as the alphasynucleinopathies. Interestingly common variation at the *SNCA* locus has been associated with MSA risk (Scholz et al., 2009, Ross et al., 2010). Two studies did not identify any *SNCA* multiplications in a combined total of 258 MSA patients (Lincoln et al., 2007, Ahn et al., 2008). Although the number of assessed samples may be small, these findings suggest that *SNCA* dosage is not a common cause of MSA. It is speculated that PD or DLB may be cause by lysosomal dysfunction, however, MSA may be caused by the oligodendrocytic changes

*SNCA* multiplication is not a common cause of sporadic or hereditary PD.

detected in Japan (Sekine et al., 2010).

sufficient to result in the parkinsonian phenotype.

**2.2 The frequency of** *SNCA* **multiplications in PD** 

**2.3** *SNCA* **multiplications in multiple system atrophy** 

in myelin basic protein (Wenning et al., 2008).

**2.1 Sporadic PD and** *SNCA* **duplication** 


Table 1. The clinical manifestations and prevalence of *SNCA* duplication and triplication

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Hope AD, Myhre R, Kachergus J, Lincoln S, Bisceglio G, Hulihan M, Farrer MJ (2004) Alpha-

Ibanez P, Bonnet AM, Debarges B, Lohmann E, Tison F, Pollak P, Agid Y, Durr A, Brice A

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Lewis J, Melrose H, Bumcrot D, Hope A, Zehr C, Lincoln S, Braithwaite A, He Z,

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### **2.4 The Synuclein family in Parkinson disease**

The *SNCA* gene is located on chromosome 4q21-22 and is associated with susceptibility to PD and DLB. Alpha-synclein has two paralogous genes, beta- (*SNCB*; MIM#602569) and gamma-synuclein (*SNCG*; MIM#602998) with which it shares a highly conserved N-terminal domain. *SNCB* is located on chromosome 5q35, and *SNCG* is located on chromosome 10q23 associated with breast and ovarian cancer (Ji et al., 1997, Goedert, 2001). All three synuclein genes are highly expressed in brain; thalamus, substantia nigra, caudate nucleus, and amygdala (Lavedan, 1998, Lavedan et al., 1998). A phylogenic tree indicates that alpha- and beta- synucleins are related more closely to each other than to gamma-synuclein (Lavedan, 1998). Interestingly, two putative pathogenic mutations in *SNCB* are reported to cause DLB, however no significant co-segregation with disease could be shown and no other studies have identified these variants (Ohtake et al., 2004). A murine model with over-expressed gamma-synuclein is reported as a PD model with motor deficits (Ninkina et al., 2009). Our recent studies on common variation in the synuclein family of genes also suggested association for variants in both *SNCA* and *SNCG* with diffuse LB disease (Nishioka et al., 2010). Given these findings, it is postulated that there is a connection between not only *SNCA*, but also *SNCB* and *SNCG* and susceptibility to PD, however multiplications of the *SNCB* and *SNCG* loci have not yet been observed.

### **3. Conclusion and future work**

Research focused on copy number variation has made remarkable progress in recent years. Genome-wide studies for copy number variants (CNV) indicate 1447 copy number variable regions (CNVRs) (Redon et al., 2006). Presumably, many of these CNV polymorphisms result in differential expression levels of proteins and dictate the phenotypic presentation at the individual level. Interestingly in Alzheimer disease multiplications of the *APP* gene have also been identified in families with autosomal dominantly inherited forms of the disease (Cabrejo et al., 2006, Rovelet-Lecrux et al., 2006). Robust and comprehensive studies are now warranted for CNV across the genome and may not only help develop new treatments for PD but perhaps several other neurodegenerative diseases.

### **4. References**


The *SNCA* gene is located on chromosome 4q21-22 and is associated with susceptibility to PD and DLB. Alpha-synclein has two paralogous genes, beta- (*SNCB*; MIM#602569) and gamma-synuclein (*SNCG*; MIM#602998) with which it shares a highly conserved N-terminal domain. *SNCB* is located on chromosome 5q35, and *SNCG* is located on chromosome 10q23 associated with breast and ovarian cancer (Ji et al., 1997, Goedert, 2001). All three synuclein genes are highly expressed in brain; thalamus, substantia nigra, caudate nucleus, and amygdala (Lavedan, 1998, Lavedan et al., 1998). A phylogenic tree indicates that alpha- and beta- synucleins are related more closely to each other than to gamma-synuclein (Lavedan, 1998). Interestingly, two putative pathogenic mutations in *SNCB* are reported to cause DLB, however no significant co-segregation with disease could be shown and no other studies have identified these variants (Ohtake et al., 2004). A murine model with over-expressed gamma-synuclein is reported as a PD model with motor deficits (Ninkina et al., 2009). Our recent studies on common variation in the synuclein family of genes also suggested association for variants in both *SNCA* and *SNCG* with diffuse LB disease (Nishioka et al., 2010). Given these findings, it is postulated that there is a connection between not only *SNCA*, but also *SNCB* and *SNCG* and susceptibility to PD, however multiplications of the

Research focused on copy number variation has made remarkable progress in recent years. Genome-wide studies for copy number variants (CNV) indicate 1447 copy number variable regions (CNVRs) (Redon et al., 2006). Presumably, many of these CNV polymorphisms result in differential expression levels of proteins and dictate the phenotypic presentation at the individual level. Interestingly in Alzheimer disease multiplications of the *APP* gene have also been identified in families with autosomal dominantly inherited forms of the disease (Cabrejo et al., 2006, Rovelet-Lecrux et al., 2006). Robust and comprehensive studies are now warranted for CNV across the genome and may not only help develop new treatments for

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**21** 

*Japan* 

 **Gene Family:** 

**Gene Duplication and** 

Shintaro Iwashita and Naoki Osada

**Retrotransposon Insertion** 

*Iwaki Meisei University / National Institute of Genetics* 

**Bucentaur (Bcnt)1**

Members of multiple gene families in higher organisms allow for more refined cellular signaling networks and structural organization toward more stable physiological homeostasis. Gene duplication is one the most powerful ways of providing an opportunity to create a novel gene(s) because a novel function might be acquired without the loss of the original gene function (Ohno, 1970). Gene duplication can result from unequal crossing over by recombination, retroposition of cDNA, or whole-genome duplication. Furthermore, a replication-based mechanism of change in gene copy number has been proposed recently (Hastings et al., 2009). Gene duplication generated by retroposition is frequently accompanied by deleterious effects because the insertion of cDNA into the genome is nearly random or unlinks the original gene location resulting in an alteration of the original vital functions of the target genes. Thus retroelements such as transposable elements and endogenous retroviruses have been thought of as "selfish". On the other hand, gene duplication caused by unequal crossing over generally results in tandem alignment, which less frequently disrupts the functions of other genes. Recent genome-wide studies have demonstrated that retroelements can definitely contribute to the creation of individual novel genes and the modulation of gene expression, which allows for the dynamic diversity of biological systems, such as placental evolution (Rawn & Cross, 2008). It is now recognized that tandem duplication and retroposition are among the key factors that initiate the creation of novel gene family members (Brosius, 2005; Sorek, 2007; Kaessmann, 2010). By these mechanisms, species-specific gene duplication can lead to species-specific gene functions, which might contribute to species-specific phenotypes (Zhang, 2003). For example, many genes derived from retroelements are expressed in mammalian placentas, and species-specific gene duplication has occurred multiple times during placental evolution (Rawn & Cross, 2008). If a combination of tandem gene duplication and retroposition of cDNA occurs, there is a good possibility for the creation of a novel gene(s)

1Although the vertebrate *Bcnt* (Bucentaur) gene is officially called *Cfdp1* (craniofacial developmental protein 1), its biological function remains unclear. So far, solid evidence that the gene is involved in craniofacial development has not been provided except for its unique expression during mouse tooth development (Diekwisch et al., 1999). The authors are concerned that a "wrong" naming may have caused confusion concerning the function of the *Bcnt*/*Cfdp1* gene. Thus we use the names *Bcnt*/*Cfdp1*,

**1. Introduction** 

*p97Bcnt/Cfdp2* and *p97Bcnt-2* in this article.

in Greek sporadic and autosomal dominant Parkinson's disease: identification of two novel LRRK2 variants. Eur J Neurol 14:7-11.

Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, Llorens V, Gomez Tortosa E, del Ser T, Munoz DG, de Yebenes JG (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164-173.
