Nousiainen et al. (2008) found that 6 of 12 Finnish patients with congenital arthrogryposis with anterior horn cell disease (CAAHD; 611890) were compound heterozygous for the Fin(Major) mutation in GLE1 (603371.0001) and a 2051T-C transition in exon 16 that changed ile684 to thr (I684T). Nousiainen et al. (2008) also found compound heterozygosity for these mutations in a patient with prolonged survival after birth who had initially been diagnosed with severe infantile spinal muscular atrophy (see 253300) but lacked SMN gene deletion.
In 2 sibs, born of consanguineous parents from northeastern Finland, with CAAHD, Paakkola et al. (2018) identified a homozygous c.2051T-C transition (c.2051T-C, NM_001003722) in the GLE1 gene, resulting in an I684T substitution in the C-terminal region that is important for nuclear localization. The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. The variant was found in heterozygous state in 2 of 615 Finnish individuals (frequency of 0.00163). It was also found in the ExAC database, with a slightly higher frequency among Finns (0.0006048) compared to the overall frequency (3.3 x 10(-5)). Patient fibroblasts showed decreased nuclear levels of GLE1 protein compared to controls.
