ClinVar

In 2 Pakistani brothers (family AGS114) who died at age 2 years with Aicardi-Goutieres syndrome (AGS8; 619486), Uggenti et al. (2020) identified homozygosity for a c.631G-A transition (c.631G-A, NM_173491.3) in the LSM11 gene, resulting in a gly211-to-ser (G211S) substitution at a highly conserved residue. Their unaffected first-cousin parents were heterozygous for the mutation, which was not found in public variant databases. RT-qPCR in patient fibroblasts revealed enrichment for aberrantly polyadenylated forms of replication-dependent histone (RDH) mRNAs derived from different histone clusters. Similar changes were observed after siRNA knockdown of LSM11 in HEK293T, HCT116, and U2OS cells. Histone expression analysis showed reduced levels of HIST1H1E (142220), encoding the linker histone H1.4, in patient-derived fibroblasts compared to controls. Genomewide transcript expression analysis revealed a global increase in polyadenylated RDH mRNA transcripts in patient cells, with a concomitant reduction in mature nonpolyadenylated RDH gene transcripts. The authors concluded that G211S is a loss-of-function variant that disturbs RDH pre-mRNA processing. An ex vivo assay of interferon signaling status in patient blood showed upregulation of interferon-stimulated genes (ISGs), and there was increased expression of ISGs in patient fibroblasts. Histone subtype-specific antibodies revealed a marked reduction in the ratio of linker H1.4 to H1.2 in patient cells compared to controls, whereas the levels of core histones showed no difference. Wide-field microscopy and immunofluorescence demonstrated an altered nuclear distribution of CGAS (613973) in patient fibroblasts compared to controls, and patient cells also exhibited an increased frequency of misshapen nuclei, including nuclear membrane herniations with intense foci of CGAS.