In 42 individuals with pontocerebellar hypoplasia type 2 (PCH2A; 277470), Budde et al. (2008) identified homozygosity for a 919G-T transversion in the TSEN54 gene, resulting in an ala307-to-ser (A307S) substitution. This mutation is likely due to a single founder event estimated by Budde et al. (2008) to have occurred at least 11 to 16 generations ago. This region of the protein is conserved in mammals and chicken but is not highly conserved in lower organisms. Analysis of 451 Dutch and 279 German control DNA samples yielded no homozygous and only 5 Dutch and 1 German heterozygous genotypes. Additionally, Budde et al. (2008) screened 136 healthy unrelated individuals from Volendam; no homozygous individuals and only 2 heterozygous individuals were identified. Thus, the allele frequency of the 919G-T variant in the PCH2 subjects was 0.884, counting the Volendam subjects as a single data point, and that in the control population was 0.004. These data strongly suggested that the TSEN54 locus is responsible for most cases of PCH2.
Budde et al. (2008) also found the 919G-T mutation in 3 individuals with pontocerebellar hypoplasia type 4 (PCH4; 225753), in isolation on 3 alleles (with compound heterozygosity in 2; see 608755.0003, 608755.0004) and once in a complex mutation with another missense substitution (608755.0002).
Cassandrini et al. (2010) identified a homozygous A307S mutation in 7 affected individuals from 6 unrelated Italian families with PCH2A. Two additional patients had a heterozygous A307S mutation: 1 patient with a PCH2A phenotype in whom the second mutation could not be detected, and another patient with a more severe phenotype (PCH4) who was compound heterozygous for A307S and a truncating mutation (608755.0005). Thus, A307S accounted for 16 (89%) of 18 mutant alleles, and haplotype analysis suggested a founder effect.
In a patient with pontocerebellar hypoplasia type 5 (PCH5; 610204), Namavar et al. (2011) identified compound heterozygosity for the common A307S mutation and a splice site mutation (608755.0006).
