ABSTRACT
OBJECTIVE: To identify the unknown genetic cause in a large pedigree previously classified with a distinct form of axonal Charcot-Marie-Tooth disease type 2G (CMT2G) and to explore its transcriptional consequences. METHODS: Clinical reevaluation of the pedigree was performed, followed by linkage analysis with the redefined disease statuses, and whole genome and exome sequencing. The impact of the mutation was investigated by immunoblotting and transcriptome sequencing. RESULTS: Thirteen affected individuals over 3 generations displayed mild and quiescent lower-limb axonal sensorimotor neuropathy. Magnetic resonance imaging (MRI) of lower-limb musculature systematically showed fatty atrophy in clinical and subclinical mutation carriers. We redefined the disease-linked region to chr9q31.3-q34.2 and subsequently identified a novel missense variant in the E3 ubiquitin-protein ligase LRSAM1 (p.Cys694Tyr). Unlike previous reports, we demonstrated in patients' lymphoblasts that the mutation does not influence overall protein levels of LRSAM1, nor of its ubiquitylation target TSG101. The mutation is associated with several transcriptional changes, including a significant upregulation of another E3 ubiquitin-protein ligase, NEDD4L, and of TNFRSF21, a key regulator of axonal degeneration. INTERPRETATION: Our findings demonstrate that the isolated genetic entity CMT2G is caused by a missense mutation in LRSAM1 and should be reclassified as CMT2P. MRI of lower-limb musculature can be used to detect minimal signs of the disease. Transcriptome analysis of patients' cells highlights novel molecular players associated with LRSAM1 dysfunction, and reveals pathways and therapeutic targets shared with amyotrophic lateral sclerosis and Alzheimer disease. Ann Neurol 2016;80:823-833.
Subject(s)
Charcot-Marie-Tooth Disease/genetics , Endosomal Sorting Complexes Required for Transport/metabolism , Receptors, Tumor Necrosis Factor/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Adult , Aged , Aged, 80 and over , Female , High-Throughput Nucleotide Sequencing , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Mutation, Missense , Nedd4 Ubiquitin Protein Ligases , Neural Conduction/genetics , Neural Conduction/physiology , Pedigree , Up-RegulationSubject(s)
Carcinoma, Merkel Cell/pathology , Neoplasm Regression, Spontaneous , Skin Neoplasms/pathology , Aged, 80 and over , Biopsy , CD3 Complex/metabolism , Carcinoma, Merkel Cell/metabolism , Carcinoma, Merkel Cell/surgery , Female , Humans , Magnetic Resonance Imaging , Skin Neoplasms/metabolism , Skin Neoplasms/surgeryABSTRACT
Schnitzler's syndrome is a rare combination of chronic urticaria, fever of unknown origin, disabling bone pain, and monoclonal gammopathy. We report a case with an unusual radiological manifestation as a solitary sclerotic lesion of the right iliac bone. Its main features on conventional radiography, computed tomography, and magnetic resonance imaging are described, and the main radiological differential diagnoses are discussed to help with the characterization of this syndrome, which requires a combination of clinical, laboratory, and radiological data. On the other hand, although our patient had an excellent clinical response to anakinra, the sclerotic lesion remained unchanged on follow-up X-ray examinations.
