Compound heterozygosity for lossâ ofâ function GARS variants results in a multisystem developmental syndrome that includes severe growth retardation

Aminoacylâ tRNA synthetases (ARSs) are ubiquitously expressed enzymes that ligate amino acids onto tRNA molecules. Genes encoding ARSs have been implicated in myriad dominant and recessive disease phenotypes. Glycylâ tRNA synthetase (GARS) is a bifunctional ARS that charges tRNAGly in the cytoplasm and mitochondria. GARS variants have been associated with dominant Charcotâ Marieâ Tooth disease but have not been convincingly implicated in recessive phenotypes. Here, we describe a patient from the NIH Undiagnosed Diseases Program with a multisystem, developmental phenotype. Wholeâ exome sequence analysis revealed that the patient is compound heterozygous for one frameshift (p.Glu83Ilefs*6) and one missense (p.Arg310Gln) GARS variant. Using in vitro and in vivo functional studies, we show that both GARS variants cause a lossâ ofâ function effect: the frameshift variant results in depleted protein levels and the missense variant reduces GARS tRNA charging activity. In support of GARS variant pathogenicity, our patient shows striking phenotypic overlap with other patients having ARSâ related recessive diseases, including features associated with variants in both cytoplasmic and mitochondrial ARSs; this observation is consistent with the essential function of GARS in both cellular locations. In summary, our clinical, genetic, and functional analyses expand the phenotypic spectrum associated with GARS variants.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138288/1/humu23287-sup-0001-text.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138288/2/humu23287.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138288/3/humu23287_am.pd

Distal myopathies a review: Highlights on distal myopathies with rimmed vacuoles

Distal myopathies are a group of heterogeneous disorders classified into one broad category due to the presentation of weakness involving the distal skeletal muscles. The recent years have witnessed increasing efforts to identify the causative genes for distal myopathies. The identification of few causative genes made the broad classification of these diseases under "distal myopathies" disputable and added some enigma to why distal muscles are preferentially affected. Nevertheless, with the clarification of the molecular basis of specific conditions, additional clues have been uncovered to understand the mechanism of each condition. This review will give a synopsis of the common distal myopathies, presenting salient facts regarding the clinical, pathological, and molecular aspects of each disease. Distal myopathy with rimmed vacuoles, or Nonaka myopathy, will be discussed in more detail

A preclinical trial of sialic acid metabolites on distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy, a sugar-deficient myopathy: a review

Distal myopathy with rimmed vacuoles (DMRV), also called hereditary inclusion body myopathy (hIBM), is a moderately progressive hereditary muscle disorder affecting young adults. DMRV/hIBM is characterized clinically by muscle atrophy and weakness initially involving the distal muscles, and pathologically by the presence of small angular fibers, formation of rimmed vacuoles and deposition of various proteins in the muscle fibers. This disease is known to be caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene, which encodes the essential enzyme in sialic acid biosynthesis, leading to a reduction of sialic acid levels in the serum and skeletal muscles of affected patients. As it is a metabolic disease, metabolite supplementation is theoretically one of the therapeutic options. In this review, recent animal models for DMRV/hIBM are briefly characterized followed by a focus on the administration of sialic acid metabolites as a reliable therapeutic option to DMRV/hIBM with the following points highlighted: the property of compounds, the pharmacokinetic metabolism in vivo, and the therapeutic effects on the DMRV/hIBM mouse model

Cortical atrophy and hypofibrinogenemia due to FGG and TBCD mutations in a single family: a case report

Abstract Background Blended phenotypes or co-occurrence of independent phenotypically distinct conditions are extremely rare and are due to coincidence of multiple pathogenic mutations, especially due to consanguinity. Hereditary fibrinogen deficiencies result from mutations in the genes FGA, FGB, and FGG, encoding the three different polypeptide chains that comprise fibrinogen. Neurodevelopmental abnormalities have not been associated with fibrinogen deficiencies. In this study, we report an unusual patient with a combination of two independently inherited genetic conditions; fibrinogen deficiency and early onset cortical atrophy. Case presentation The study describes a male child from consanguineous family presented with hypofibrinogenemia, diffuse cortical atrophy, microcephaly, hypertonia and axonal motor neuropathy. Through a combination of homozygosity mapping and exome sequencing, we identified bi-allelic pathogenic mutations in two genes: a homozygous novel truncating mutation in FGG (c.554del; p.Lys185Argfs*14) and a homozygous missense mutation in TBCD (c.1423G > A;p.Ala475Thr). Loss of function mutations in FGG have been associated with fibrinogen deficiency, while the c.1423G > A mutation in TBCD causes a novel syndrome of neurodegeneration and early onset encephalopathy. Conclusions Our study highlights the importance of homozygosity mapping and exome sequencing in molecular prenatal diagnosis, especially when multiple gene mutations are responsible for the phenotype

Rimmed vacuoles in Becker muscular dystrophy have similar features with inclusion myopathies.

Rimmed vacuoles in myofibers are thought to be due to the accumulation of autophagic vacuoles, and can be characteristic in certain myopathies with protein inclusions in myofibers. In this study, we performed a detailed clinical, molecular, and pathological characterization of Becker muscular dystrophy patients who have rimmed vacuoles in muscles. Among 65 Becker muscular dystrophy patients, we identified 12 patients who have rimmed vacuoles and 11 patients who have deletions in exons 45-48 in DMD gene. All patients having rimmed vacuoles showed milder clinical features compared to those without rimmed vacuoles. Interestingly, the rimmed vacuoles in Becker muscular dystrophy muscles seem to represent autophagic vacuoles and are also associated with polyubiquitinated protein aggregates. These findings support the notion that rimmed vacuoles can appear in Becker muscular dystrophy, and may be related to the chronic changes in muscle pathology induced by certain mutations in the DMD gene

A recurrent de novo missense mutation in UBTF causes developmental neuroregression

UBTF (upstream binding transcription factor) exists as two isoforms; UBTF1 regulates rRNA transcription by RNA polymerase 1, whereas UBTF2 regulates mRNA transcription by RNA polymerase 2. Herein, we describe 4 patients with very similar patterns of neuroregression due to recurrent de novo mutations in UBTF (GRCh37/hg19, NC_000017.10: g.42290219C\u3eT, NM_014233.3: c.628G\u3eA) resulting in the same amino acid change in both UBTF1 and UBTF2 (p. Glu210Lys [p. E210K]). Disease onset in our cohort was at 2.5 to 3 years and characterized by slow progression of global motor, cognitive and behavioral dysfunction. Notable early features included hypotonia with a floppy gait, high-pitched dysarthria and hyperactivity. Later features included aphasia, dystonia, and spasticity. Speech and ambulatory ability were lost by the early teens. Magnetic resonance imaging showed progressive generalized cerebral atrophy (supratentorial\u3einfratentorial) with involvement of both gray and white matter. Patient fibroblasts showed normal levels of UBTF transcripts, increased expression of pre-rRNA and 18S rRNA, nucleolar abnormalities, markedly increased numbers of DNA breaks, defective cell-cycle progression, and apoptosis. Expression of mutant human UBTF1 in Drosophila neurons was lethal. Although no loss-of-function variants are reported in the Exome Aggregation Consortium(ExAC) database and Ubtf-/- is early embryonic lethal in mice, Ubtf+/- mice displayed only mild motor and behavioral dysfunction in adulthood. Our data underscore the importance of including UBTF E210K in the differential diagnosis of neuroregression and suggest that mainly gain-of-function mechanisms contribute to the pathogenesis of the UBTF E210K neuroregression syndrome

Corrigendum: A recurrent de novo missense mutation in UBTF causes developmental neuroregression [Human Molecular Genetics, 27, 4, (2018) (691-705)] doi: 10.1093/hmg/ddx435

The name of one of the authors of this article contained an error in the original version: Harper B. Fauni\u27s name was misstated as \u27Fauni Harper\u27. This has now been corrected in the online version. The authors wish to apologize for this mistake

Clinical, genetic, and structural characterization of a novel TUBB4B tubulinopathy

Microtubules are cytoskeletal polymers of ⍺/β-tubulin heterodimers essential for a wide range of cellular processes. Pathogenic variations in microtubule-encoding genes (e.g., TUBB4B, which encodes the β-4B tubulin isotype) are responsible for a wide spectrum of cerebral malformations, collectively referred to as “tubulinopathies.” The phenotypic manifestation of TUBB4B-associated tubulinopathy is Leber congenital amaurosis with early-onset deafness (LCAEOD), an autosomal dominant syndrome characterized by photoreceptor and cochlear cell loss; all known patients have pathogenic variations in amino acid R391. We present the clinical and molecular genetics findings of a 16-year-old female with a de novo missense variant in exon 1 of TUBB4B, c.32 A > G (p.Gln11Arg; Q11R). In addition to hearing loss and hyperopia without retinal abnormalities, our proband presented with two phenotypes of unknown genetic etiology, i.e., renal tubular Fanconi Syndrome (FS) and hypophosphatemic rickets (HR). The Q11R variant expands the genetic basis of early sensory hearing loss; its consequences with respect to microtubule structure are described. A mechanistic explanation for the FS and rickets, involving microtubule-mediated translocation of transporter proteins to and from the apical membrane of renal proximal tubular cells, is proposed