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Biomedical subjects

J Johnston

Publications and source records attributed to J Johnston.

At least 37 records · Page 2Linked to original sources
PubMed2001

Human thymic stromal lymphopoietin preferentially stimulates myeloid cells.

The sequence of a novel hemopoietic cytokine was discovered in a computational screen of genomic databases, and its homology to mouse thymic stromal lymphopoietin (TSLP) suggests that it is the human orthologue. Human TSLP is proposed to signal through a heterodimeric receptor complex that consists of a new member of the hemopoietin family termed human TSLP receptor and the IL-7R alpha-chain. Cells transfected with both receptor subunits proliferated in response to purified, recombinant human TSLP, with induced phosphorylation of Stat3 and Stat5. Human TSLPR and IL-7Ralpha are principally coexpressed on monocytes and dendritic cell populations and to a much lesser extent on various lymphoid cells. In accord, we find that human TSLP functions mainly on myeloid cells; it induces the release of T cell-attracting chemokines from monocytes and, in particular, enhances the maturation of CD11c(+) dendritic cells, as evidenced by the strong induction of the costimulatory molecules CD40 and CD80 and the enhanced capacity to elicit proliferation of naive T cells.

Amino Acid Sequence↗
PubMed2001

Barth's syndrome-like disorder: a new phenotype with a maternally inherited A3243G substitution of mitochondrial DNA (MELAS mutation).

An Argentine male child died at 4.5 years of age of a lethal mitochondrial disease associated with a MELAS mutation and a Barth syndrome-like presentation. The child had severe failure to thrive from the early months and for approximately two years thereafter. In addition, the patient had severely delayed gross motor milestones, marked muscle weakness, and dilated cardiomyopathy that progressed to congestive heart failure. He also had persistently elevated urinary levels of 3-methylglutaconic and 2-ethylhydracrylic acids and low blood levels of cholesterol. Detailed histopathologic evaluation of the skeletal muscle biopsy showed high activity of succinate dehydrogenase, a generalized decrease of COX activity, and abundant ragged-red fibers. Electron microscopic studies revealed multiple mitochondrial abnormalities in lymphocytes and monocytes, in the striated muscle, and in the postmortem samples (muscle, heart, liver, and brain). Biochemical analysis showed a pronounced and constant lactic acidosis, and abnormal urinary organic acid excretion (unchanged in the fasting and postprandial states). In addition, in CSF there was a marked increase of lactate and beta-hydroxybutyrate (beta-HOB) and also a high systemic ratio beta-HOB/acetoacetate. Enzymatic assay of the respiratory chain in biopsied muscle showed 10% of complex I activity and 24% of complex IV activity compared with controls. Molecular studies of the mitochondrial genome revealed an A to G mutation at nucleotide pair 3243 in mitochondrial DNA, a well-known pathogenetic mutation (MELAS mutation) in all the patient's tissues and also in the blood specimens of the probands mother and sibs (4 of 5). The diagnosis of MELAS mutation was reinforced by the absence of an identifiable mutation in the X-linked G4.5 gene of the propositus. The present observation gives additional evidence of the variable clinical expression of mtDNA mutations in humans and demonstrates that all clinical variants deserve adequate investigation to establish a primary defect. It also suggests adding Barth-like syndrome to the list of phenotypes with the MELAS mutation.

3-Hydroxybutyric Acid↗
PubMed2001

Morbidity and mortality in rheumatoid arthritis patients with prolonged and profound therapy-induced lymphopenia.

OBJECTIVE: Therapies that deplete lymphocytes often improve symptoms in patients with otherwise refractory autoimmune disease but may result in long-term lymphopenia, the consequences of which are uncertain. To assess the impact of prolonged lymphopenia on morbidity and mortality, we studied patients who had previously received lymphocytotoxic monoclonal antibody (mAb) therapy for rheumatoid arthritis (RA). METHODS: Fifty-three patients who received the lymphocytotoxic mAb CAMPATH-1H between 1991 and 1994 in the United Kingdom were assessed for mortality and infectious and malignant morbidity, by interview and case-note review. In addition, patients were monitored via the National Health Service Central Registry, to verify notification of death. Peripheral blood lymphocyte subsets were analyzed by flow cytometry. A retrospective, matched-cohort study of mortality was also performed with 102 control subjects selected from the European League Against Rheumatism database, which comprises patients with rheumatic disorders who have received immunosuppressive drugs. RESULTS: There was profound and persistent peripheral blood lymphopenia in the mAb-treated patients, affecting predominantly the CD4+ subset. Median CD4+, CD8+, and CD19+ peripheral blood lymphocyte counts at 73-84 months after therapy were 185 cells/microl, 95 cells/microl, and 115 cells/microl, respectively. At a median followup of 71 months (range 14-90), 13 patients had died (24.5%), compared with 18% of the matched controls, providing a mortality rate ratio of 1.45 (95% confidence interval 0.65-3.13). During 283 patient-years of followup, there were 36 infections classified as major (12.7 per 100 patient-years). The causes of death and the spectrum of infections documented were similar to those expected in a hospital-based RA cohort. Patients who received more than 1 course of therapy had more severe lymphopenia than did patients who received a single course, but this did not have an impact on mortality or morbidity. CONCLUSION: Despite the occurrence of profound and long-lasting lymphopenia following treatment with antilymphocyte mAb therapy for RA, this therapy is not associated with a large excess of mortality nor with an unusual spectrum of infections, at least during a medium-term period of followup. These data are also relevant to patients receiving lymphocytotoxic mAb therapy for other indications, and to patients receiving other lymphodepleting therapies such as autologous stem cell transplantation.

Aged↗
PubMed2001

Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver.

Systemic administration of a recombinant adenovirus encoding the human interferon-beta gene (H5.110CMVhIFN-beta) results in transduction of hepatocytes and detectable circulating levels of IFN-beta protein. In preclinical studies in mice, we noticed a distinctly nonlinear dose response, with low levels of virus (1-3 x 10(10) viral particles) yielding barely detectable levels of IFN-beta but with a higher viral dose (1 x 10(11) particles) resulting in disproportionately high IFN-beta levels. Further studies showed that transgene expression levels from low viral doses could be dramatically enhanced by coadministering an unrelated recombinant adenovirus (H5.110CMVlacZ), suggesting that there was a viral dose threshold effect for efficient viral transduction and/or IFN-beta expression. This enhancement of reporter expression by a nonreporter adenovirus, effective upon coadministration, was further enhanced by preadministration of H5.110CMVlacZ (up to 8 h), but was ineffective if the helper virus was administered as little as 5 min after the H5.110CMVhIFN-beta reporter virus. Our data suggest that the reticuloendothelial system plays a role in this threshold effect, such that low doses of virus are efficiently taken up by the RES/Kupffer cells without leading to appreciable transgene expression, whereas high doses saturate these cells and are able to productively transduce hepatocytes. A better understanding of this phenomenon could have an impact on gene therapy clinical trial safety and efficacy.

Adenoviridae↗
PubMed2001

TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. impaired B cell maturation in mice lacking BLyS.

BLyS and APRIL have similar but distinct biological roles, mediated through two known TNF receptor family members, TACI and BCMA. We show that mice treated with TACI-Ig and TACI-Ig transgenic mice have fewer transitional T2 and mature B cells and reduced levels of circulating immunoglobulin. TACI-Ig treatment inhibits both the production of collagen-specific Abs and the progression of disease in a mouse model of rheumatoid arthritis. In BLyS-deficient mice, B cell development is blocked at the transitional T1 stage such that virtually no mature B cells are present, while B-1 cell numbers are relatively normal. These findings further elucidate the roles of BLyS and APRIL in modulating B cell development and suggest that BLyS is required for the development of most but not all mature B cell populations found in the periphery.

Animals↗
PubMed2001

Movement-related cortical potentials associated with progressive muscle fatigue in a grasping task.

OBJECTIVE: The present research was aimed to further address the general empirical question regarding the behavioral and neurophysiological indices and mechanisms that contribute to and/or compensate for muscle fatigue. In particular, we examined isometric force production, EMG, and EEG correlates of progressive muscle fatigue while subjects performed a grasping task. METHODS: Six neurologically healthy subjects were instructed to produce and maintain 70% of maximum voluntary contraction (MVC) for a total of 5 s in a sequence of 120 trials using a specially designed grip dynamometer. Three components of movement-related potentials (Bereitschaftspotential, BP, Motor potential, MP, and Movement-monitoring potential, MMP) were extracted from continuous EEG records and analyzed with reference to behavioral indicators of muscle fatigue. RESULTS: Experimental manipulations induced muscle fatigue that was demonstrated by decreases in both MVC values and mean force levels produced concomitant to increases in EMG root mean square (RMS) amplitude with respect to baseline levels, and EMG slope. EEG data revealed a significant increase in MP amplitude at precentral (Cz and FCz) and contralateral (C3) electrode sites, and increases in BP amplitude at precentral (Cz and FCz) electrode sites. CONCLUSIONS: The increases in EMG amplitude, EMG slope, and MP amplitudes suggest a possible link between the control signal originating in the motor cortex and activity level of the alpha-motoneuron pool as a function of progressive muscle fatigue. Overall, the data demonstrate that progressive muscle fatigue induced a systematic increase in the electrocortical activation over the supplementary motor and contralateral sensorimotor areas as reflected in the amplitude of movement-related EEG potentials.

Adolescent↗
PubMed2001

Immediate-early protooncogene expression and liver function following various extents of partial hepatectomy in the rat.

Immediate-early protooncogenes (IEP) are thought to play an important role in hepatocyte replication. Whether the extent of their expression correlates with the strength of the proliferative stimulus and subsequent regenerative activity has yet to be documented in vivo. Data are also lacking with respect to the level at which liver disease is associated with biochemical evidence of hepatic dysfunction. Thus, the objectives of this study were to determine whether a correlation exists between IEP gene mRNA expression and varying extents of partial hepatectomy (PHx) and to document the extent of resection required to result in increases in serum bilirubin levels. Eighty-nine adult, male Sprague-Dawley rats underwent either sham surgery or 20%, 35%, 55%, 70% or 90% PHx. Postoperatively, rats were killed (N = 3-6/group) at 15 and 30 mins and 8 and 24 hrs for c-fos, c-jun, and c-myc mRNA expression by northern blot analyses. Rats killed at 24 hrs also had hepatic regenerative activity documented by [3H]thymidine incorporation into hepatic DNA and serum bilirubin determinations. While c-fos mRNA expression at 15 mins and c-myc mRNA expression at 8 hrs after PHx did not correlate with the extent of PHx (r2 = 0.478 and 0.018, respectively), a weak correlation existed between c-jun mRNA expression at 30 mins and the extent of PHx (r2 = 0.662, P < 0.05). In terms of IEP mRNA expression and hepatic regenerative activity, a strong correlation existed between c-fos mRNA expression and [3H]thymidine incorporation (r2 = 0.851, P < 0.01) but not c-jun or c-myc mRNA expression. Compared to sham operated controls, [3H]thymidine incorporation was 2.0x, 3.4x, 3.2x, 7.8x, and 2.2x increased following 20%, 35%, 55%, 70%, and 90% PHx, respectively. Serum bilirubin levels remained unchanged until 70% PHx, when they increased from baseline values of 0.54+/-0.05 mg/dl to 1.02+/-0.15 mg/dl (P < 0.05). A further increase occurred following 90% PHx (1.83+/-0.30 mg/dl, P < 0.01). In conclusion these findings indicate that c-fos mRNA expression 15 mins after PHx correlates with hepatic regenerative activity but not the strength of the regenerative stimulus and that hepatic parenchymal loss of 55-70% must occur prior to the detection of elevated serum bilirubin levels. The results also indicate that relative to a 70% PHx, 90% PHx is associated with decreased rather than increased hepatic regenerative activity.

Animals↗
PubMed2001

An analysis of early renal transplant protocol biopsies--the high incidence of subclinical tubulitis.

To investigate the possibility that we have been underestimating the true incidence of acute rejection, we began to perform protocol biopsies after kidney transplantation. This analysis looks at the one-week biopsies. Between March 1 and October 1, 1999, 100 adult patients undergoing cadaveric kidney or kidney/pancreas transplantation, or living donor kidney transplantation, underwent 277 biopsies. We focused on the subset of biopsies in patients without delayed graft function (DGF) and with stable or improving renal function, who underwent a biopsy 8.2+/-2.6 d (range 3-18 d) after transplantation (n = 28). Six (21%) patients with no DGF and with stable or improving renal function had borderline histopathology, and 7 (25%) had acute tubulitis on the one-week biopsy. Of the 277 kidney biopsies, there was one (0.4%) serious hemorrhagic complication, in a patient receiving low molecular weight heparin; she ultimately recovered and has normal renal function. Her biopsy showed Banff 1B tubulitis. In patients with stable or improving renal allograft function early after transplantation, subclinical tubulitis may be present in a substantial number of patients. This suggests that the true incidence of rejection may be higher than is clinically appreciated.

Adult↗
PubMed2001

Human myeloid dendritic cells transduced with an adenoviral interleukin-10 gene construct inhibit human skin graft rejection in humanized NOD-scid chimeric mice.

Human myeloid DC were generated from peripheral blood mononuclear cells by monocyte adhesion and subsequent culture with rhGM-CSF and rhIL-4. We transduced immature (day 5 of culture) myeloid DC with an E1-deleted replication-deficient adenoviral vector encoding the cytokine IL-10 (AdV IL-10) and a control adenovirus MX-17 (AdV MX 17). Human DC transduced with AdV IL-10 showed inhibition of the mixed leukocyte culture, reduced cell surface expression of co-stimulatory molecules (CD80/CD86) and were unable to produce the potent allo-stimulatory cytokine, interleukin-12. In order to test the in vivo properties of these cells a humanized immunodeficient mouse skin transplantation model was developed. Immunodeficient NOD-scid mice were engrafted with human skin, reconstituted via intraperitoneal injection with allogeneic mononuclear cells (MNC) mixed with 1 x 10(6) DC that were autologous to the skin donor and that had been transduced with either AdV IL-10 or AdV MX-17. Skin grafts were removed at day 7 and 14 after reconstitution and studied histologically for evidence of rejection. In animals that received DC modified with AdV IL-10 there was reduced skin graft rejection as characterized by reduced mononuclear cell infiltration and less dermo-epidermal junction destruction compared with those animals that received DC modified with the control virus alone. Injection of equivalent numbers of donor-derived fibroblasts transduced with AdV IL-10 were ineffective at modifying rejection of skin grafts. Immunosuppressive cytokine gene therapy targeting human DC is a novel means of inhibition of the alloimmune response.

Adenoviridae↗
PubMed2001

The community integration measure: development and preliminary validation.

OBJECTIVE: To present a new measure of community integration, the Community Integration Measure (CIM), and to offer preliminary information about its psychometric properties. DESIGN: Validation study. SETTING: Community. PARTICIPANTS: Ninety-two participants placed in 3 subgroups (brain injury survivors, n = 41; significant others, n = 36; college students, n = 15). MAIN OUTCOME MEASURES: The distributional properties, factor structure, internal consistency reliability, content validity, discriminant validity, concurrent validity, and construct validity of the CIM. RESULTS: All items correlated positively with each other and with the total score. Principal components factor analysis confirmed a 1-factor structure, which explained 44.1% of the variance. Internal consistency reliability, using Cronbach's alpha, was.87. Content validity was assured by the development procedure, correspondence with the theoretical model, and direct use of consumer language. Discriminant validity was supported by the CIM's ability to differentiate between subsamples. Criterion validity was supported by using correlations with the Community Integration Questionnaire. Construct validity was supported by correlations with the Interpersonal Support Evaluation List. CONCLUSION: The CIM offers a brief, easily administered measure of community integration that conforms to an empirically derived theoretical model and is psychometrically sound.

Activities of Daily Living↗
PubMed2001

Does diabetes target ganglion neurones? Progressive sensory neurone involvement in long-term experimental diabetes.

Targeting of dorsal root ganglia by diabetes could account for the selective sensory abnormalities that patients with early diabetic polyneuropathy develop. In this work, we addressed survival, phenotype and gene expression in sensory neurones in lumbar dorsal root ganglia in a long-term model of experimental streptozotocin-induced diabetes in rats, designed to reflect human disease. Motor and sensory conduction slowing developed early, by the 2-month time point. At 2 months, sensory neurones had no detectable alterations in their calibre or gene expression, assessed using quantitative in situ hybridization studies for mRNA markers that included alpha CGRP, beta CGRP, NFM, t alpha 1-tubulin, SP, VIP, B50 (GAP43), galanin, somatostatin, PACAP, HSP27, c-jun, SNAP 25, p75, TrkA, TrkB and TrkC. By 12 months, however, diabetics had developed neurone perikaryal and distal axon atrophy, accompanied by generalized downregulation of mRNA expression, particularly of CGRP transcripts, PACAP, SP, NFM, p75, trkA and trkC. With the exception of HSP-27, no elevation in mRNAs that increase after injury, such as VIP, galanin, CCK, PACAP, B50 and t alpha 1-tubulin, was observed and constitutive levels, when detectable, trended towards lower rather than increased levels. There was relative preservation of neurone numbers at 12 months; only a non-significant trend towards fewer diabetic neurones was detected using a rigorous and systematic physical dissector counting approach through the entire L5 ganglia. There was no change in the relative populations of CGRP- and SP-immunoreactive neurones. Our findings indicate that even long-term experimental diabetes is associated with relative preservation of sensory neurone populations, but the neurones are atrophic and their gene expression is altered. This pattern of change differs from that following axotomy, implies a degenerative rather than an injury phenotype and has important implications for how such neurones might be rescued.

Animals↗
PubMed2001

Immunohistochemical localization of Pax2 and associated proteins in the developing kidney of mice with renal hypoplasia.

Pax2 has been identified as a key regulatory protein associated with renal developmental malformations. The purpose of this study was to determine whether Pax2 protein expression, and that of other proteins important for normal renal development, is abnormally distributed in the prenatal kidney of the Brachyrrhine (Br) mouse that displays heritable renal hypoplasia. Embryonic 3H1 +/+ and Br/Br mice were collected between E11.0 and E18.0. Routine light microscopy and immunohistochemical analysis using antibodies to Pax2, E-cadherin, fibronectin, laminin, and Type IV collagen were applied to sequential tissue sections. E-cadherin stained consistently in the renal tubules of both normal and mutant animals. Whereas the initial expression of Pax2 corresponded between normal and mutant kidneys, it became progressively limited to the nephrogenic zone in +/+ animals, while distributing erratically in the Br/Br kidney. Fibronectin was not expressed in the normal nephrogenic zone but remained abundantly distributed throughout the Br/Br kidney. Luminin and Type IV collagen staining revealed a deficiency in renal vasculature formation in Br/Br kidneys. Results suggest that initial morphological differentiation occurs normally in the Br kidney but that subsequent nephric formation is associated with abnormal distribution of Pax2 and ECM proteins. (J Histochem Cytochem 49:1081-1097, 2001)

Animals↗
PubMed2001

Defining community integration of persons with brain injuries as acculturation: a Canadian perspective.

In this study, the AIMS, a measure of community integration developed from acculturation theory, was used to explore the various ways that people with brain injuries, a smaller cultural or minority group, are involved with the larger cultural group and to evaluate rehabilitation outcome (i.e., reintegration into the community). Specifically, the AIMS assesses whether the needs of individuals with brain injuries in a number of areas are identified and supported in a way that supports community participation. In addition, the opinions of persons with a brain injury regarding their level of community integration were compared to the opinions of individuals who knew them well. The results of this study indicate that while a large proportion of the participants with brain injuries were integrated in traditional areas of service delivery such as medical services, housing and social activity, their disability-related needs were not being identified and supported adequately in the areas of spirituality and productive activity.

Acculturation↗
PubMed2000

Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function.

Cytokines are important in the regulation of haematopoiesis and immune responses, and can influence lymphocyte development. Here we have identified a class I cytokine receptor that is selectively expressed in lymphoid tissues and is capable of signal transduction. The full-length receptor was expressed in BaF3 cells, which created a functional assay for ligand detection and cloning. Conditioned media from activated human CD3+ T cells supported proliferation of the assay cell line. We constructed a complementary DNA expression library from activated human CD3+ T cells, and identified a cytokine with a four-helix-bundle structure using functional cloning. This cytokine is most closely related to IL2 and IL15, and has been designated IL21 with the receptor designated IL21 R. In vitro assays suggest that IL21 has a role in the proliferation and maturation of natural killer (NK) cell populations from bone marrow, in the proliferation of mature B-cell populations co-stimulated with anti-CD40, and in the proliferation of T cells co-stimulated with anti-CD3.

Amino Acid Sequence↗
PubMed2000

Spiritual issues associated with traumatic-onset disability.

PURPOSE: The present study used a qualitative approach to discover the concepts used by people with a sudden-onset disability to express issues of spirituality. Using a cross-sectional time frame, the study sought to understand how spiritual issues were experienced at the onset of a disability from the perspective of the disabled person him or herself. The study also compared the perceptions of brain injury respondents to spinal cord injury respondents. METHOD: The qualitative approach was chosen to capture a detailed understanding of perceptions about spirituality, and the relationship of the disability to the disabled person's spiritual beliefs. The sample consisted of 16 individuals, all of whom had experienced a spinal cord injury or a brain injury. RESULTS: The main findings of the study were as follows: (1) Participants recovering from a disability described spiritual issues relating to five themes which arose directly from the data (awareness, closeness, trust, purpose, vulnerability) and relating to three relationships found throughout the literature on spirituality (intrapersonal, interpersonal and transpersonal). These eight dimensions can be combined to form a matrix, which serves as a framework for considering spiritual issues associated with disability; and (2) There were differences in the spiritual concepts described by the participants with brain injury compared to those with spinal cord injury. In particular, those with brain injuries seemed to place greater emphasis on the importance of their families, and to be more aware of the need for trust in view of their memory deficits. CONCLUSIONS: These results represent one of the earliest attempts to take an empirical approach to the development of theory in the area of spirituality and disability. Building on theory developed in other populations (palliative care and ageing), the study offers a theoretical model for clinicians, educators and researchers to better understand spirituality in the context of disability.

Acute Disease↗
PubMed2000

TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease.

B cells are important in the development of autoimmune disorders by mechanisms involving dysregulated polyclonal B-cell activation, production of pathogenic antibodies, and co-stimulation of autoreactive T cells. zTNF4 (BLyS, BAFF, TALL-1, THANK) is a member of the tumour necrosis factor (TNF) ligand family that is a potent co-activator of B cells in vitro and in vivo. Here we identify two receptors for zTNF4 and demonstrate a relationship between zTNF4 and autoimmune disease. Transgenic animals overexpressing zTNF4 in lymphoid cells develop symptoms characteristic of systemic lupus erythaematosus (SLE) and expand a rare population of splenic B-Ia lymphocytes. In addition, circulating zTNF4 is more abundant in NZBWF1 and MRL-lpr/lpr mice during the onset and progression of SLE. We have identified two TNF receptor family members, TACI and BCMA, that bind zTNF4. Treatment of NZBWF1 mice with soluble TACI-Ig fusion protein inhibits the development of proteinuria and prolongs survival of the animals. These findings demonstrate the involvement of zTNF4 and its receptors in the development of SLE and identify TACI-Ig as a promising treatment of autoimmune disease in humans.

Amino Acid Sequence↗
PubMed2000

Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia.

Inactivation of the beta4 subunit of the calcium channel in the mouse neurological mutant lethargic results in a complex neurological disorder that includes absence epilepsy and ataxia. To determine the role of the calcium-channel beta4-subunit gene CACNB4 on chromosome 2q22-23 in related human disorders, we screened for mutations in small pedigrees with familial epilepsy and ataxia. The premature-termination mutation R482X was identified in a patient with juvenile myoclonic epilepsy. The R482X protein lacks the 38 C-terminal amino acids containing part of an interaction domain for the alpha1 subunit. The missense mutation C104F was identified both in a German family with generalized epilepsy and praxis-induced seizures and in a French Canadian family with episodic ataxia. These coding mutations were not detected in 255 unaffected control individuals (510 chromosomes), and they may be considered candidate disease mutations. The results of functional tests of the truncated protein R482X in Xenopus laevis oocytes demonstrated a small decrease in the fast time constant for inactivation of the cotransfected alpha1 subunit. Further studies will be required to evaluate the in vivo consequences of these mutations. We also describe eight noncoding single-nucleotide substitutions, two of which are present at polymorphic frequency, and a previously unrecognized first intron of CACNB4 that interrupts exon 1 at codon 21.

Amino Acid Sequence↗