A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-47 (SCA47) is caused by heterozygous mutation in the PUM1 gene (607204) on chromosome 1p35.

Heterozygous mutation in the PUM1 gene also causes NEDMSF (620719), a more severe neurologic disorder with onset in infancy.

Spinocerebellar ataxia-47 (SCA47) is an autosomal dominant neurologic disorder characterized by slowly progressive gait ataxia. Additional features usually include diplopia, dysarthria, and dysmetria. Brain imaging shows atrophy of the cerebellar vermis. The age at onset is variable: affected members in 1 reported family developed symptoms as adults in their thirties or forties, whereas 1 unrelated girl had onset in the first decade (Gennarino et al., 2018).

For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Gennarino et al. (2018) reported a family (family X) in which 9 members spanning 3 generations had adult-onset spinocerebellar ataxia, which the authors called adult-onset 'Pumilio-1-related cerebellar ataxia (PRCA).' Clinical details were available for 3 living sisters in their fifties. All 3 developed slowly progressive cerebellar ataxia in their thirties or forties, characterized by gait ataxia, dysmetria, dysarthria, and, in some cases, diplopia. Brain imaging showed progressive mild cerebellar vermian atrophy. Their deceased father developed ataxia in his fifties. Other affected family members, most of whom were deceased, reportedly had a similar phenotype.

Gennarino et al. (2018) also reported an unrelated 9-year-old girl (P10) who showed chorea, gait ataxia, and fine-motor incoordination from the age of 5 years. She also had dysarthria, spasticity, and ballismus. She was noted to have early motor delay and short stature, but did not have intellectual disability or seizures. Brain imaging was normal at age 6.

The transmission pattern of SCA47 in the family reported by Gennarino et al. (2018) was consistent with autosomal dominant inheritance with incomplete penetrance. The heterozygous mutation in the PUM1 gene that was identified in a girl with early-onset SCA47 occurred de novo.

In affected members of a family (family X) with SCA47, Gennarino et al. (2018) identified a heterozygous missense mutation in the PUM1 gene (T1035S; 607204.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The affected father's sister, who was unaffected at age 80 years, also carried the mutation, indicating incomplete penetrance. DNA from other affected family members was not available. Patient cells showed a 25% decrease in PUM1 protein levels, and a 40 to 50% increase in ATXN1 (601556) and E2F3 (600427) levels compared to controls. In vitro studies showed that overexpression of the T1035S variant was unable to reduce ATXN1 and E2F3 levels, consistent with a loss of repressor function.

In a girl (P10) with early-onset SCA47, Gennarino et al. (2018) identified a de novo heterozygous missense mutation in the PUM1 gene (R1139W; 607204.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. She also carried a variant of uncertain significance in the XPR1 gene (605237). Although patient cells were not available for study, the mutation was predicted to result in a 48% reduction in PUM1 protein levels compared to wildtype, consistent with haploinsufficiency. In vitro transfection studies in HEK293 cells showed that overexpression of the R1139W variant was unable to reduce ATXN1 and E2F3, indicating that it impaired the repression activity of PUM1. Hamosh (2024) noted that the R1139W variant is present in 2 of 833,094 alleles in the gnomAD database (frequency of 2.4 x 10(-6)).

Gennarino et al. (2018) found that the missense mutations identified in patients with SCA47 reduced PUM1 protein levels to varying degrees. PUM1 levels were reduced by about 50% in the patient (P10) with onset of the disorder in early childhood, and by about 25% in the less severe adult-onset SCA47 cases (family X). The levels of known PUM1 targets increased accordingly, indicating that changes in protein levels tracked with phenotypic severity. HEK293 cells transfected with PUM1 bearing a mutation in the PUM-HD domain (R1139W and T1035S) were unable to suppress levels of ATXN1 and E2F3, 2 well-known PUM1 targets, consistent with a loss of repressor function. Overexpression of each mutant in dissociated mouse hippocampal neurons suppressed dendritic arborization somewhat compared to empty vector, but only the T1035S variant approached the degree of suppression seen with wildtype, consistent with the milder phenotype of adult-onset SCA47.

Gennarino et al. (2015) found that heterozygous Pum1 +/- mice had increased levels of Atxn1 mRNA and protein levels in the cerebrum and cerebellum compared to controls, indicating that Pum1 directly regulates Atxn1 levels in the mouse brain. Pum1-null mice were significantly smaller in body and brain size compared to controls and to Pum1 +/- mice. The loss of 1 copy of the Pum1 gene was sufficient to cause progressive motor performance, and the motor incoordination was even more pronounced in Pum1-null mice. Loss of Pum1 resulted in progressive cerebellar dysfunction, manifest as gait and stride ataxia with a spinocerebellar ataxia-like neurodegeneration with gross and fine motor impairment. Neuropathologic examination showed progressive Purkinje cell degeneration and loss of dendritic arborization in mutant mice. The features were similar to those observed in mouse models of SCA1 (164400), which is caused by abnormal accumulation of Atxn1 due to an expanded polyglutamine repeat within that gene. The motor phenotype, Purkinje cell degeneration, and dendritic arborization defects could be mitigated by decreasing Atxn1 protein levels using genetic crossing of Pum1 +/- mice with Atxn1 +/- mice. In addition, overexpression of wildtype Pum1 in Atxn1 mutant mice resulted in a reduction of Atxn1 levels in the cerebellum. The findings elucidated a posttranscriptional regulatory mechanism that regulates ATXN1 levels and could putatively play a role in disease.

Follow-up analysis of Pum1-null mutant mice by Gennarino et al. (2018) showed that they were born at a lower frequency than expected and showed hyperactivity, marked growth defects, spontaneous seizures, abnormal EEG, cerebellar hypoplasia, and Purkinje cell degeneration.