Genomic deletions upstream of lamin B1 lead to atypical autosomal dominant leukodystrophy

Abstract

ObjectiveClinical, radiologic, and molecular analysis of patients with genomic deletions upstream of the LMNB1 gene.MethodsDetailed neurologic, MRI examinations, custom array comparative genomic hybridization (aCGH) analysis, and expression analysis were performed in patients at different clinical centers. All procedures were approved by institutional review boards of the respective institutions.ResultsFive patients from 3 independent families presented at ages ranging from 32 to 52 years with neurologic symptoms that included progressive hypophonia, upper and lower limb weakness and spasticity, and cerebellar dysfunction and MRIs characterized by widespread white matter alterations. Patients had unique nonrecurrent deletions upstream of the LMNB1, varying in size from 250 kb to 670 kb. Deletion junctions were embedded in repetitive elements. Expression analysis revealed increased LMNB1 expression in patient cells.ConclusionsOur findings confirmed the association between LMNB1 upstream deletions and leukodystrophy previously reported in a single family, expanding the phenotypic and molecular description of this condition. Although clinical and radiologic features overlapped with those of autosomal dominant leukodystrophy because of LMNB1 duplications, patients with deletions upstream of LMNB1 had an earlier age at symptom onset, lacked early dysautonomia, and appeared to have lesser involvement of the cerebellum and sparing of the spinal cord diameter on MRI. aCGH analysis defined a smaller minimal critical region required for disease causation and revealed that deletions occur at repetitive DNA genomic elements. Search for LMNB1 structural variants (duplications and upstream deletions) should be an integral part of the investigation of patients with autosomal dominant adult-onset leukodystrophy.

Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes

“…The real prevalence of this ultra-rare pathology remains still uncertain [4] with sporadic new clinical case reports from different geographical areas, suggesting a possible heterogeneity in the first clinical manifestations and signs [5][6][7][8][9][10]. In majority of ADLD cases, the first clinical manifestations are related to autonomic dysfunction from bladder or bowel dysfunction to orthostatic hypotension, temperature dysregulation, and anhidrosis [11][12][13][14][15].…”

Lessons from the analysis of TAD boundary deletions in normal population

“…The minimal critical region required for the disease phenotype, spanning about 167 kb, disrupts the 3'-boundary of TAD containing LMNB1. It is assumed that the TAD disruption allows ectopic action of a brain specific regulatory element, called Enh-B, on LMNB1 promoter (Nmezi et al 2019). Surprisingly, we identified 38 benign or likely-benign deletions encompassing the 3'-boundary of LMNB1-containing TAD, using data from the 36 Hi-C assays.…”

“…Deletions disrupting the boundary between TADs containing EPHA4 and PAX3 abolish its insulator-effect and allow improper regulation of PAX3 by a cluster of limb-specific enhancers from the adjacent TAD (Lupiáñez et al 2015a). Many others examples of this mechanism have been reported, including TADs containing LMNB1 or SOX9 genes (Nmezi et al 2019) (Franke et al 2016).…”

The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD

“…Autosomal dominant leukodystrophy (ADLD), a fatal adult onset demyelination disorder, is caused by gene duplication of LMNB1 or by genomic deletions upstream of the LMNB1 gene [ 49 , 50 ]. Both genetic alterations induce the overexpression of lamin B1 in oligodendrocytes, specialized myelin producing cells in the central nervous system [ 51 ].…”