Katherine Johnson

Jackson Laboratory

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Volker Straub

Newcastle upon Tyne Hospitals NHS Foundation Trust

Ana Töpf

Newcastle University

Lauren Phillips

Hospital for Sick Children

Monkol Lek

Yale University

Daniel G. MacArthur

Murdoch Children's Research Institute

Liwen Xu

University of Science and Technology of China

Jonathan Baets

Antwerp University Hospital

Willem De Ridder

University of Antwerp

Marta Bértoli

Centre for Life

Shahriar Nafissi

Shariati Hospital

Cooperative Institutions

Newcastle University

Inserm

Sorbonne Université

University of Antwerp

University College London

Assistance Publique – Hôpitaux de Paris

National Institutes of Health

University of Washington

Instituto de Salud Carlos III

University of Oxford

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Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation

Neurology (2019)

Willem De Ridder Asfar S. Azmi Christoph S. Clemen Ludwig Eichinger Andreas Hofmann

To assess the clinical, radiologic, myopathologic, and proteomic findings in a patient manifesting a multisystem proteinopathy due to a homozygous valosin-containing protein gene (VCP) mutation previously reported to be pathogenic in the heterozygous state.We studied a 36-year-old male index patient and his father, both presenting with progressive limb-girdle weakness. Muscle involvement was assessed by MRI and muscle biopsies. We performed whole-exome sequencing and Sanger sequencing for segregation analysis of the identified p.Arg159His VCP mutation. To dissect biological disease signatures, we applied state-of-the-art quantitative proteomics on muscle tissue of the index case, his father, 3 additional patients with VCP-related myopathy, and 3 control individuals.The index patient, homozygous for the known p.Arg159His mutation in VCP, manifested a typical VCP-related myopathy phenotype, although with a markedly high creatine kinase value and a relatively early disease onset, and Paget disease of bone. The father exhibited a myopathy phenotype and discrete parkinsonism, and multiple deceased family members on the maternal side of the pedigree displayed a dementia, parkinsonism, or myopathy phenotype. Bioinformatic analysis of quantitative proteomic data revealed the degenerative nature of the disease, with evidence suggesting selective failure of muscle regeneration and stress granule dyshomeostasis.We report a patient showing a multisystem proteinopathy due to a homozygous VCP mutation. The patient manifests a severe phenotype, yet fundamental disease characteristics are preserved. Proteomic findings provide further insights into VCP-related pathomechanisms.

Sanger sequencing

Muscle weakness

10.1212/wnl.0000000000008763

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Citations (16)

The Initiation of Respiration in Asphyxia Neonatorum. A Clinical and Experimental Study Incorporating Fœtal Blood Analyses and a Consideration of Important Methods of Resuscitation

Proceedings of the Royal Society of Medicine (1937)

Robert A. Wilson Marcus A. Torrey Katherine Johnson

Asphyxia Neonatorum

Artificial respiration

10.1177/003591573703001206

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Citations (3)

The effect of exercise on gastrointestinal symptoms and body composition at different phases of the menstrual cycle

Graduate Journal of Sport Science Coaching Management and Rehabilitation (2024)

L. Bass Katherine Johnson S.R. Rowland Joanne Barrett S. N. Dixon

Women commonly experience bloating, stomach cramps, water retention, and weight gain at the beginning of their menstrual cycle, which cause fluctuations in body composition through extracellular changes, this may affect osmotic pressure, leading to gastrointestinal (GI) symptoms. The aim of this study was to investigate the effect of the menstrual cycle phase on extracellular changes and GI symptoms in females in response to exercise. Seven healthy premenopausal female recreational athletes (maximal O2 consumption: 50 ± 5.8 ml·kg-1) performed two running trials in an experimental crossover design during two distinct phases of the menstrual cycle, early follicular phase (EFP) and the mid-luteal phase (MLP). Each trial consisted of 120 min of running, 60 min at 110% lactate threshold and 60 min at 90%. Determination of cycle was calculated from calendar-based counting and urinary ovulation detection kits. The EFP was determined by self-reporting onset of menses. The day before each trial, participants followed a low FODMAP diet and completed a gastrointestinal symptom rating scale questionnaire. On the morning of the trial, a standard breakfast was consumed, upon arrival at the laboratory, body composition was recorded. Each hour, finger prick samples were taken to measure lactate and ensure performance did not exceed maximum, every 15 minutes, a visual analog scale (VAS) of subjective ratings between 0-10 cm of gut comfort was taken. Data was analysed using mean and standard deviation (subsequent statistical analysis will be conducted if an n = 10 is reached prior to the conference). During exercise, participants experienced a higher prevalence of GI issues throughout the EFP compared with the MLP. The most common complaints reported from the VAS were nausea; EFP 1 ± 1 cm, MLP 0 ± 0 cm. Flatulence; EFP 4 ± 3 cm, MLP 1 ± 1 cm, and stomach cramps; EFP 3 ± 2 cm, MLP 1 ± 1 cm. Total body weight (TBW) differences were noted between the EFP and MLP. TBW EFP pre-exercise was higher than MLP pre-exercise phase EFP pre-exercise: 38.7 ± 2.8 L compared to MLP pre-exercise at 35.8 ±5.5 L. Similar differences were demonstrated with extra cellular water pre-exercise EFP; 16.1 ± 1.1 L MLP; 15.2 ±1.0 L. During the EFP fluid retention is known to be higher than the MLP, and results are as expected. While the data suggests a seemingly minimal variation in Gl symptoms, individually, there appears to be a higher level of difference. More gastrointestinal symptoms were reported during exercise, which is consistent with the findings. There is a slight difference in GI symptoms between the EFP and MLP at this stage, indicating a slight shift in total body water.

Menstruation

10.19164/gjsscmr.v1i3.1519

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P.175Detection and interpretation of variants in dystroglycanopathy-causing genes in a cohort of 1,566 patients with unexplained limb-girdle muscle weakness

Neuromuscular Disorders (2019)

Ana Töpf Ana Casasús Rita Barresi Katherine Johnson Magdalena Mroczek

Muscle weakness

Proximal muscle weakness

10.1016/j.nmd.2019.06.230

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First clinical and myopathological description of a myofibrillar myopathy with congenital onset and homozygous mutation in FLNC

Human Mutation (2020)

Heike Kölbel Andreas Roos Peter F. M. van der Ven Teresinha Evangelista Kay Nolte

Filamin C (encoded by the FLNC gene) is a large actin-cross-linking protein involved in shaping the actin cytoskeleton in response to signaling events both at the sarcolemma and at myofibrillar Z-discs of cross-striated muscle cells. Multiple mutations in FLNC are associated with myofibrillar myopathies of autosomal-dominant inheritance. Here, we describe for the first time a boy with congenital onset of generalized muscular hypotonia and muscular weakness, delayed motor development but no cardiac involvement associated with a homozygous FLNC mutation c.1325C>G (p.Pro442Arg). We performed ultramorphological, proteomic, and functional investigations as well as immunological studies of known marker proteins for dominant filaminopathies. We show that the mutant protein is expressed in similar quantities as the wild-type variant in control skeletal muscle fibers. The proteomic signature of quadriceps muscle is altered and ultrastructural perturbations are evident. Moreover, filaminopathy marker proteins are comparable both in our homozygous and a dominant control case (c.5161delG). Biochemical investigations demonstrate that the recombinant mutant protein is less stable and more prone to degradation by proteolytic enzymes than the wild-type variant. The unusual congenital presentation of the disease clearly demonstrates that homozygosity for mutations in FLNC severely aggravates the phenotype.

10.1002/humu.24062

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Citations (12)

Studies of sympathetic nervous system (SNS) dysregulation in major depression (MDD)

Biological Psychiatry (1989)

Philip J. Wilner Katherine Johnson Jaw-Sy Chen John A. Sweeney J. John Mann

Depression

Sympathetic nervous system

10.1016/0006-3223(89)91893-3

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Citations (1)

Investigating the functional coupling between Rad50 ATP active sites

Katherine Johnson

Source

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POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy

Annals of Neurology (2019)

John Vissing Katherine Johnson Ana Töpf Shahriar Nafissi Jordi Díaz‐Manera

Objective The Popeye domain containing 3 ( POPDC3) gene encodes a membrane protein involved in cyclic adenosine monophosphate (cAMP) signaling. Besides gastric cancer, no disease association has been described. We describe a new muscular dystrophy associated with this gene. Methods We screened 1,500 patients with unclassified limb girdle weakness or hyperCKemia for pathogenic POPDC3 variants. Five patients carrying POPDC3 variants were examined by muscle magnetic resonance imaging (MRI), muscle biopsy, and cardiac examination. We performed functional analyses in a zebrafish popdc3 knockdown model and heterologous expression of the mutant proteins in Xenopus laevis oocytes to measure TREK‐1 current. Results We identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe, and p.Arg261Gln) in 5 patients from 3 ethnically distinct families. Variants affected highly conserved residues in the Popeye (p.Leu155 and p.Leu217) and carboxy‐terminal (p.Arg261) domains. The variants were almost absent from control populations. Probands’ muscle biopsies were dystrophic, and serum creatine kinase levels were 1,050 to 9,200U/l. Muscle weakness was proximal with adulthood onset in most patients and affected lower earlier than upper limbs. Muscle MRI revealed fat replacement of paraspinal and proximal leg muscles; cardiac investigations were unremarkable. Knockdown of popdc3 in zebrafish, using 2 different splice‐site blocking morpholinos, resulted in larvae with tail curling and dystrophic muscle features. All 3 mutants cloned in Xenopus oocytes caused an aberrant modulation of the mechano‐gated potassium channel, TREK‐1. Interpretation Our findings point to an important role of POPDC3 for skeletal muscle function and suggest that pathogenic variants in POPDC3 are responsible for a novel type of autosomal recessive limb girdle muscular dystrophy. ANN NEUROL 2019;86:832–843

Limb-girdle muscular dystrophy

Dysferlin

10.1002/ana.25620

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Citations (32)

Bi-allelicTTC5variants cause delayed developmental milestones and intellectual disability

Journal of Medical Genetics (2020)

Arisha Rasheed Evren Gümüş Maha S. Zaki Katherine Johnson Humera Manzoor

Intellectual disability syndromes (IDSs) with or without developmental delays affect up to 3% of the world population. We sought to clinically and genetically characterise a novel IDS segregating in five unrelated consanguineous families.Clinical analyses were performed for eight patients with intellectual disability (ID). Whole-exome sequencing for selected participants followed by Sanger sequencing for all available family members was completed. Identity-by-descent (IBD) mapping was carried out for patients in two Egyptian families harbouring an identical variant. RNA was extracted from blood cells of Turkish participants, followed by cDNA synthesis and real-time PCR for TTC5.Phenotype comparisons of patients revealed shared clinical features of moderate-to-severe ID, corpus callosum agenesis, mild ventriculomegaly, simplified gyral pattern, cerebral atrophy, delayed motor and verbal milestones and hypotonia, presenting with an IDS. Four novel homozygous variants in TTC5: c.629A>G;p.(Tyr210Cys), c.692C>T;p.(Ala231Val), c.787C>T;p.(Arg263Ter) and c.1883C>T;p.(Arg395Ter) were identified in the eight patients from participating families. IBD mapping revealed that c.787C>T;p.(Arg263Ter) is a founder variant in Egypt. Missense variants c.629A>G;p.(Tyr210Cys) and c.692C>T;p.(Ala231Val) disrupt highly conserved residues of TTC5 within the fifth and sixth tetratricopeptide repeat motifs which are required for p300 interaction, while the nonsense variants are predicted to decrease TTC5 expression. Functional analysis of variant c.1883C>T;p.(Arg395Ter) showed reduced TTC5 transcript levels in accordance with nonsense-mediated decay.Combining our clinical and molecular data with a recent case report, we identify the core and variable clinical features associated with TTC5 loss-of-function variants and reveal the requirement for TTC5 in human brain development and health.

Sanger sequencing

Corpus Callosum Agenesis

Ventriculomegaly

Nonsense

10.1136/jmedgenet-2020-106849

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Citations (8)

Improved Criteria for the Classification of Titin Variants in Inherited Skeletal Myopathies

Journal of Neuromuscular Diseases (2020)

Marco Savarese Mridul Johari Katherine Johnson Meharji Arumilli Annalaura Torella

Extensive genetic screening results in the identification of thousands of rare variants that are difficult to interpret. Because of its sheer size, rare variants in the titin gene (TTN) are detected frequently in any individual. Unambiguous interpretation of molecular findings is almost impossible in many patients with myopathies or cardiomyopathies.To refine the current classification framework for TTN-associated skeletal muscle disorders and standardize the interpretation of TTN variants.We used the guidelines issued by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) to re-analyze TTN genetic findings from our patient cohort.We identified in the classification guidelines three rules that are not applicable to titin-related skeletal muscle disorders; six rules that require disease-/gene-specific adjustments and four rules requiring quantitative thresholds for a proper use. In three cases, the rule strength need to be modified.We suggest adjustments are made to the guidelines. We provide frequency thresholds to facilitate filtering of candidate causative variants and guidance for the use and interpretation of functional data and co-segregation evidence. We expect that the variant classification framework for TTN-related skeletal muscle disorders will be further improved along with a better understanding of these diseases.

Medical genetics

Genetic diagnosis

10.3233/jnd-190423

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Citations (22)