Susan E. Holmes

A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease–like 2

We recently described a disorder termed Huntington disease–like 2 (HDL2) that completely segregates with an unidentified CAG/CTG expansion in a large pedigree (W). We now report the cloning of this expansion and its localization to a variably spliced exon of JPH3 (encoding junctophilin-3), a gene involved in the formation of junctional membrane structures.

A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder

In a large Scottish pedigree, a balanced translocation t(1;11)(q42.1;q14.3) segregates with major mental illness, including schizophrenia, bipolar disorder, and recurrent major depression. The translocation is predicted to result in the loss of the C-terminal region of the protein product of Disrupted In SChizophrenia 1 (DISC1), a gene located on 1q42.1. Since this initial discovery, DISC1 has been functionally implicated in several processes, including neurodevelopment. Based on the genetic and functional evidence that DISC1 may be associated with schizophrenia, we sequenced portions of DISC1 in 28 unrelated probands with schizophrenia and six unrelated probands with schizoaffective disorder, ascertained as part of a large sibpair study. We detected a 4 bp deletion at the extreme 3′ end of exon 12 in a proband with schizophrenia. The mutation was also present in a sib with schizophrenia, a sib with schizoaffective disorder, and the unaffected father, while the mutation was not detected in 424 control individuals. The mutation is predicted to cause a frameshift and encode a truncated protein with nine abnormal C-terminal amino acids. The truncated transcript is detectable, but at a reduced level, in lymphoblastoid cell lines from three of four mutation carriers. These findings are consistent with the possibility that mutations in the DISC1 gene can increase the risk for schizophrenia and related disorders.

A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion.

Huntingtons disease (HD) is an autosomal dominant disorder characterized by abnormalities of movement, cognition, and emotion and selective atrophy of the striatum and cerebral cortex. While the etiology of HD is known to be a CAG trinucleotide repeat expansion, the pathways by which this mutation causes HD pathology remain unclear. We now report a large pedigree with an autosomal dominant disorder that is clinically similar to HD and that arises from a different CAG expansion mutation. The disorder is characterized by onset in the fourth decade, involuntary movements and abnormalities of voluntary movement, psychiatric symptoms, weight loss, dementia, and a relentless course with death about 20 years after disease onset. Brain magnetic resonance imaging scans and an autopsy revealed marked striatal atrophy and moderate cortical atrophy, with striatal neurodegeneration in a dorsal to ventral gradient and occasional intranuclear inclusions. All tested affected individuals, and no tested unaffecteds, have a CAG trinucleotide repeat expansion of 50 to 60 triplets, as determined by the repeat expansion detection assay. Tests for the HD expansion, for all other known CAG expansion mutations, and for linkage to chromosomes 20p and 4p were negative, indicating that this mutation is novel. Cloning the causative CAG expansion mutation for this new disease, which we have termed Huntingtons disease‐like 2 (HDL2), may yield valuable insight into the pathogenesis of HD and related disorders.

Huntington's disease–like 2 is associated with CUG repeat-containing RNA foci

Huntingtons disease–like 2 (HDL2) is caused by a CAG/CTG expansion mutation on chromosome 16q24.3. The repeat falls, in the CTG orientation, within a variably spliced exon of junctophilin‐3 (JPH3). The existence of a JPH3 splice variant with the CTG repeat in 3′ untranslated region suggested that transcripts containing an expanded CUG repeat could play a role in the pathogenesis of HDL2, similar to the proposed pathogenic role of expanded CUG repeats in myotonic dystrophy type 1 (DM1). The goal of this study, therefore, was to test the plausibility of an RNA gain‐of‐function component in the pathogenesis of HDL2.

SCA-12: Tremor with cerebellar and cortical atrophy is associated with a CAG repeat expansion

Objective: To characterize the clinical and neuroradiologic features of a new spinocerebellar ataxia, SCA-12, in the index family. Background: The authors recently linked SCA-12 to a novel CAG repeat expansion on chromosome 5q31-33 that is located within the 5’ region of PPP2R2B, a gene encoding a brain-specific regulatory subunit of protein phosphatase 2A. Methods: Neurologic features of the proband and nine symptomatic relatives in the first SCA-12 family were compiled and, in some individuals, related to changes found on brain MRI or CT. Results: SCA-12 typically presented in the 4th decade of life with action tremor of the head or arms (present in 10/10 of the affected individuals). Hyperreflexia (8/10) was a common feature, and cerebellar signs (8/10), including ataxia, dysmetria, and dysarthria, developed gradually but were less prominent and disabling than cerebellar dysfunction in other SCA. Subtle parkinsonian features (9/10) and dementia (2/10) were observed in later stages of SCA-12, and psychiatric symptoms, including depression, anxiety, or delusions, were present in some affected family members (4/10). Two individuals studied had nondisabling neurologic signs neonatally, including nystagmus and lower extremity dystonia. Brain images of affected individuals revealed cerebral and cerebellar atrophy. Conclusions: SCA-12 is a slowly progressive, autosomal dominant, neurodegenerative disorder that differs from other SCA in that it typically presents with action tremor in patients in their mid 30s and usually includes hyperreflexia and subtle parkinsonian signs. Cerebellar dysfunction, including gait ataxia, is relatively nondisabling, and cognitive or psychiatric disorders may occur. Neuroradiologic studies reveal atrophy of the cerebellum and cerebral cortex.

SCA12 is a rare locus for autosomal dominant cerebellar ataxia: A study of an Indian family

Spinocerebellar ataxia 12 (SCA12) is an autosomal dominant cerebellar ataxia (ADCA) described in a single family with a CAG repeat expansion in the PPP2R2B gene. We screened 247 index cases, including 145 families with ADCA, for this expansion. An expanded repeat ranging from 55 to 61 triplets was detected in 6 affected and 3 unaffected individuals at risk in a single family from India. The association of the PPP2R2B CAG repeat expansion with disease in this new family provides additional evidence that the mutation is causative. Ann Neurol 2001;49:117–121

Huntington's disease–like 2 (HDL2) in North America and Japan

Huntingtons Disease–like 2 (HDL2) is a progressive, autosomal dominant, neurodegenerative disorder with marked clinical and pathological similarities to Huntingtons disease (HD). The causal mutation is a CTG/CAG expansion mutation on chromosome 16q24.3, in a variably spliced exon of junctophilin‐3. The frequency of HDL2 was determined in nine independent series of patients referred for HD testing or selected for the presence of an HD‐like phenotype in North America or Japan. The repeat length, ancestry, and age of onset of all North American HDL2 cases were determined. The results show that HDL2 is very rare, with a frequency of 0 to 15% among patients in the nine case series with an HD‐like presentation who do not have the HD mutation. HDL2 is predominantly, and perhaps exclusively, found in individuals of African ancestry. Repeat expansions ranged from 44 to 57 triplets, with length instability in maternal transmission detected in a repeat of 33 triplets. A younger age of onset is correlated with a longer repeat length (r2 = 0.29, p = 0.0098). The results further support the evidence that the repeat expansion at the chromosome 16q24.3 locus is the direct cause of HDL2 and provide preliminary guidelines for the genetic testing of patients with an HD‐like phenotype. Ann Neurol 2004

Why is SCA12 different from other SCAs

Spinocerebellar ataxia type 12 (SCA12), now described in European-American and Asian (Indian) pedigrees, is unique among the SCAs from clinical, pathological, and molecular perspectives. Clinically, the distinguishing feature is early and prominent action tremor with variability in other signs. Pathologically, brain MRIs also suggest variability, with promi- nent cortical as well as cerebellar atrophy. Genetically, SCA12 is caused by a CAG repeat expansion that does not encode polyglutamine; we speculate that the mutation may affect expression of the gene PPP2R2B, which encodes a brain-specific regulatory subunit of the protein phosphatase PP2A.

Huntington’s disease-like 2 can present as chorea-acanthocytosis

Three patients from a previously described family with autosomal dominant chorea-acanthocytosis were found to have the CTG trinucleotide repeat expansion mutation of the junctophilin-3 gene associated with Huntington’s disease–like 2 (HDL2). One of six previously identified patients with HDL2 had acanthocytosis on peripheral blood smear, suggesting that HDL2 should be considered in the differential of chorea-acanthocytosis.

Missense mutations in the AFG3L2 proteolytic domain account for ∼1.5% of European autosomal dominant cerebellar ataxias

Spinocerebellar ataxia type 28 is an autosomal dominant form of cerebellar ataxia (ADCA) caused by mutations in AFG3L2, a gene that encodes a subunit of the mitochondrial m‐AAA protease. We screened 366 primarily Caucasian ADCA families, negative for the most common triplet expansions, for point mutations in AFG3L2 using DHPLC. Whole‐gene deletions were excluded in 300 of the patients, and duplications were excluded in 129 patients. We found six missense mutations in nine unrelated index cases (9/366, 2.6%): c.1961C>T (p.Thr654Ile) in exon 15, c.1996A>G (p.Met666Val), c.1997T>G (p.Met666Arg), c.1997T>C (p.Met666Thr), c.2011G>A (p.Gly671Arg), and c.2012G>A (p.Gly671Glu) in exon 16. All mutated amino acids were located in the C‐terminal proteolytic domain. In available cases, we demonstrated the mutations segregated with the disease. Mutated amino acids are highly conserved, and bioinformatic analysis indicates the substitutions are likely deleterious. This investigation demonstrates that SCA28 accounts for ∼3% of ADCA Caucasian cases negative for triplet expansions and, in extenso, to ∼1.5% of all ADCA. We further confirm both the involvement of AFG3L2 gene in SCA28 and the presence of a mutational hotspot in exons 15–16. Screening for SCA28, is warranted in patients who test negative for more common SCAs and present with a slowly progressive cerebellar ataxia accompanied by oculomotor signs. Hum Mutat 31:1–8, 2010.