Objective: We describe a novel congenital motor neuron disease with early demise due to respiratory insufficiency with clinical overlap with spinal muscular atrophy with respiratory distress (SMARD) type 1 but lacking a mutation in the IGHMBP2 gene.Methods: Exome sequencing was used to identify a de novo mutation in the LAS1L gene in the proband. Pathogenicity of the mutation was validated using a zebrafish model by morpholinomediated knockdown of las1l.Results: We identified a de novo mutation in the X-linked LAS1L gene in the proband (p.S477N).The mutation is in a highly conserved region of the LAS1L gene predicted to be deleterious by bioinformatic analysis. Morpholino-based knockdown of las1l, the orthologous gene in zebrafish, results in early lethality and disruption of muscle and peripheral nerve architecture. Coinjection of wild-type but not mutant human RNA results in partial rescue of the phenotype. Conclusion:We report a patient with a SMARD phenotype due to a mutation in LAS1L, a gene important in coordinating processing of the 45S pre-rRNA and maturation of the large 60S ribosomal subunit. Similarly, the IGHMB2 gene associated with SMARD type 1 has been suggested to have an important role in ribosomal biogenesis from its role in processing the 45S pre-rRNA. We propose that disruption of ribosomal maturation may be a common pathogenic mechanism linking SMARD phenotypes caused by both IGHMBP2 and LAS1L. Spinal muscular atrophy with respiratory distress (SMARD) is a rare autosomal recessive disorder of neonatal weakness and early respiratory failure (Online Mendelian Inheritance in Man [OMIM] #604320). 1 SMARD was first described in 1974 as a variant of WerdnigHoffmann disease (spinal muscular atrophy type I) but is distinguished by the prominence of early respiratory failure and distal muscle weakness or joint contractures.2 Since discovery of the IGHMBP2 gene as a cause for SMARD, 3 appreciation of the clinical and genetic heterogeneity has been increasing.2,4,5 IGHMBP2 is a ubiquitously expressed helicase that colocalizes with factors controlling RNA splicing in the cytosol and nucleus. 6 A role for IGHMBP2 in translation has been proposed based on colocalization in the cytoplasm with ribosomal proteins and ribosomal RNA (rRNA). 6,7 As in many other disorders with motor neuron involvement, it is unclear why mutations in IGHMBP2 have a disproportionate effect on motor neurons. 8Infants presenting with a SMARD phenotype but lacking mutations in IGHMBP2 are common, accounting for up to two-thirds of reported patients. 4,9 We describe an infant who presented with distal weakness and primary respiratory failure associated with diaphragm paralysis but lacking a
Familial hemophagocytic lymphohistiocytosis type 2 (FHL2), caused by perforin 1 (PRF1), is a genetic disorder of lymphocyte cytotoxicity that usually presents in the first 2 years of life and has a poor prognosis. Late onset of FHL2 has been sporadically reported, and the mechanism is largely unknown. A newly diagnosed FHL2 patient was detected to have compound mutations in both PRF1 alleles and positive Epstein-Barr virus (EBV) infection. Her brother carried the same mutations and EBV infection status but kept healthy. To search the potential unknown mechanisms, we performed whole-exome sequencing analysis. The patient and her asymptomatic brother carried the same heterozygous missense (c.916G>A) and frameshift mutation (c.65delC) in PRF1. Germline mutation analysis demonstrated that only the proband was exclusively detected with a homozygous missense mutation (S1006L) in the PCDH18 gene, whereas others were found to have a heterozygous mutation (S1006L) of PCDH18. The calculated stability (free energy) changes showed that the mutation of PCDH18 mainly destabilized the protein structure. Furthermore, the mutation (S1006L) could lessen the PCDH18-induced inhibition of target cell activation and reduce the apoptosis of T lymphocytes. This study is the first to perform whole-exome sequencing analysis to search the potential "second-hit" mechanism that underlies the onset of FHL2. A novel type of compound heterozygous mutation has been found in PRF1. The detection of the homozygous germline mutation in PCDH18 strongly argues that the presence of a "second" germline mutation besides the PRF1 gene might be potentially an important mechanism for triggering the onset of FHL2.
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