RESUMEN
Charcot-Marie-Tooth disease (CMT) is characterised by great variability of genetic subtypes. This study aimed to assess the genetic subtypes of CMT disease in the Sardinian population. Genetic screening was performed for CMT cases (CMT1, CMT2, and hereditary neuropathy with susceptibility to pressure palsies [HNPP]). A total of 1,043 subjects (119 index cases) were evaluated. In CMT1 index cases (69/119; 58%), PMP22 duplication at 17p11.2 was the most frequent genetic diagnosis (60/69; 87%), followed by mutations in the GJB1 gene (5/69; 7.2%), in the SH3TC2 gene (3/69; 4.4%) and PMP22 Gly107Val point mutation (1/69; 1.4%). The CMT2 group (24/119; 20.1%) comprised 10/24 (41.6%) patients carrying MPZ gene Ser44Phe mutation, 6/24 (25%) with mutations in MFN2 and HSPB1, and 1/24 (4.2%) in GJB1 and LRSAM1. In the HNPP group (26/119; 21.9%), the majority of patients reported the PMP22 deletion (25/26; 96.2%). Further studies are needed to comprehend the overall picture of the disease in Mediterranean area.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Conexinas/genética , Familia , GTP Fosfohidrolasas/genética , Humanos , Italia , Proteínas Mitocondriales/genética , Mutación , Proteína P0 de la Mielina/genética , Proteínas de la Mielina/genética , Población Blanca , Proteína beta1 de Unión ComunicanteRESUMEN
Alterations of the lamin A/C (LMNA) gene are associated with different clinical entities, including disorders that affect skeletal and cardiac muscle, peripheral nerves, metabolism, bones, and disorders that cause premature aging. In this article we review the clinical and genetic characteristics of cardiac and skeletal muscle diseases related to alterations in the LMNA gene. There is no single explanation of how LMNA gene alterations may cause these disorders; however, important goals have been achieved in understanding the pathogenic effects of LMNA gene mutations on cardiac and skeletal muscle.
Asunto(s)
Lamina Tipo A/genética , Músculo Esquelético/patología , Enfermedades Musculares/genética , Enfermedades Musculares/patología , Mutación/genética , Miocardio/patología , Animales , Humanos , Enfermedades Musculares/clasificaciónRESUMEN
Mutations on the LMNA gene are responsible for an heterogeneous group of diseases. Overlapping syndromes related to LMNA gene alterations have been extensively reported. Study scope is to perform a systematic analysis of the overlapping syndromes so far described and to try to correlate the clinical features to the associated genetic alterations. We evaluated all the dominant overlapping syndromes reported by means of a PubMed search and by the analysis of the main databases containing the pathogenic LMNA gene variations and the associated diseases. Metabolic alterations in association to skeletal and/or cardiac alterations proved to be the most frequent overlap syndrome. Overlapping syndromes are mostly associated to inframe mutations in exons 1, 2, 8 and 9. These data further improve the understanding of the pathogenesis of laminopathies.
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ADN/genética , Genes Sobrepuestos , Lamina Tipo A/genética , Lipodistrofia/genética , Mutación , Análisis Mutacional de ADN , Humanos , Lamina Tipo A/metabolismo , Lipodistrofia/metabolismo , SíndromeRESUMEN
INTRODUCTION: The clinical course of late-onset Pompe disease is heterogeneous, and new clinical outcome measures are needed to evaluate enzyme replacement therapy (ERT). METHODS: We correlated the 6-Minute Walk Test (6MWT), Walton and Gardner-Medwin (WGM) score, and GSGC (Gait, Stairs, Gower, Chair) scores in 40 patients. RESULTS: At baseline, the GSGC score correlated with both WGM (P < 0.001, n = 33) and 6MWT (P < 0.001, n = 26). After 1 year of ERT, we observed a significant change in gait, stairs and chair performance on the GSGC scale. The 6MWT significantly increased from 319 to 371 meters in 32 patients, and the WGM score was reduced. CONCLUSIONS: GSGC is a group of functional tests that requires only a few minutes to perform, therefore, this score might be a good indicator to be used in future studies.
Asunto(s)
Evaluación de la Discapacidad , Terapia de Reemplazo Enzimático , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Actividad Motora/fisiología , Evaluación de Resultado en la Atención de Salud , Adulto , Edad de Inicio , Anciano , Femenino , Estudios de Seguimiento , Marcha/fisiología , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Caminata/fisiologíaRESUMEN
INTRODUCTION: LMNA gene mutations are associated with cardiac and skeletal muscle alterations. METHODS: A cohort of 21 mutated individuals was assessed with clinical and instrumental investigations over the years. RESULTS: The median observation period was 6 years. Cardiac compromise was detected in 16 patients. Bradyarrhythmias were the most frequent manifestations, followed by supraventricular arrhythmias. Two individuals suffered from nonsustained and 1 from sustained ventricular tachyarrhythmias. Dilated cardiomyopathy was detected in 3 patients. Evaluation of the frequencies of the clinical expressions showed a high probability of suffering from analogue heart compromise in study subjects bearing the same LMNA gene mutation. CONCLUSIONS: Cardiac involvement represents a very common phenotypic expression of LMNA gene mutation. Subjects sharing common genetic background seem to suffer from analogue pattern of cardiac manifestation.
Asunto(s)
Arritmias Cardíacas/genética , Cardiomiopatía Dilatada/genética , Lamina Tipo A/genética , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Patients with a partial reduction of merosin due to mutations in the laminin-α2 chain gene usually present with a mild form of congenital muscular dystrophy or a limb-girdle-like muscular dystrophy. To our knowledge, cardiac impairment has never been reported in such patients. A longitudinal study of a patient with partial laminin-α2 deficiency secondary to mutations in the LAMA2 gene revealed dilated cardiomyopathy with ventricular arrhythmias. Is this a chance association or a novel phenotype?
Asunto(s)
Arritmias Cardíacas/genética , Cardiomiopatía Dilatada/genética , Laminina/deficiencia , Mutación/genética , Fenotipo , Adulto , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/metabolismo , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/metabolismo , Sistema de Conducción Cardíaco/metabolismo , Sistema de Conducción Cardíaco/fisiopatología , Humanos , Laminina/genética , Estudios Longitudinales , MasculinoRESUMEN
INTRODUCTION: Familial dilated cardiomyopathy with conduction system defects variably associated with skeletal muscle abnormalities is frequently caused by LMNA gene mutations. METHODS: A family affected by cardiac abnormalities, either isolated or variably associated with skeletal muscle compromise, was identified. LMNA gene analysis was applied to all family members. RESULTS: A novel intron 5 (c.937-11 C > G) mutation was identified. mRNA transcription analysis was subsequently performed, and cDNA was obtained from mutated patients. It displayed an aberrant splice product featuring the insertion of 40 nucleotides from intron 5, leading to a frameshift. Computational predictions identified a cryptic splice site 40 bp upstream from the canonical site; this alternative splicing event was elicited by intronic mutation, which seems to interfere with the polypyrimidine tract of the canonical site. CONCLUSIONS: We have described the first mutation on the LMNA gene interfering with the polypyrimidine tract. Our findings underline the importance of including introns in the search for mutations.
Asunto(s)
Empalme Alternativo/genética , Intrones/genética , Lamina Tipo A/genética , Mutación/genética , Proteína de Unión al Tracto de Polipirimidina/genética , Adulto , Anciano , Secuencia de Bases , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , LinajeRESUMEN
INTRODUCTION: In this study we describe the clinical and molecular characteristics of limb-girdle muscular dystrophy (LGMD) due to LAMA2 mutations. METHODS: Five patients clinically diagnosed with LGMD and showing brain white matter hyperintensities on MRI were evaluated using laminin α2 genetic and protein testing. RESULTS: The patients had slowly progressive, mild muscular dystrophy with various degrees of CNS involvement. Epilepsy was observed in 2, and subtle symptoms of CNS involvement (mild deficit in executive functions and low IQ scores) were noted in 3 patients. Novel LAMA2 mutations were identified in all patients. The amount of laminin α2 protein in the muscle biopsies ranged from trace to about 50% compared with controls. CONCLUSIONS: This study represents the largest series of LGMD laminin α2-deficient patients and expands the clinical phenotype associated with LAMA2 mutations. The findings suggest that brain MRI could be included in the diagnostic work-up of patients with undiagnosed LGMD.
Asunto(s)
Laminina/genética , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/patología , Mutación/genética , Adolescente , Anciano , Empalme Alternativo , Secuencia de Bases , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Distrofia Muscular de Cinturas/metabolismo , Mutagénesis Insercional , Fenotipo , Sitios de Empalme de ARN , Adulto JovenRESUMEN
BACKGROUND: Heat shock protein 27 (HSP27) mutations have been reported to cause both Charcot-Marie-Tooth disease (CMT) type 2F and distal hereditary motor neuropathy (dHMN) although never previously in a single family. OBJECTIVE: To analyse clinical and electrophysiological findings obtained in a single large Sardinian family bearing the HSP27 R127W mutation. METHODS: Twenty-one members of a five generation Sardinian family have been studied, including thirteen members affected by peroneal muscular atrophy and proved heterozygous for the known HSP27 R127W mutation. Twelve patients and eight unaffected relatives were subjected to clinical examination. A standardised electrophysiological study was performed in eleven patients and six unaffected relatives. RESULTS: Mean age at onset (+/-SD) was 31.2+/-7.2 years. Mean age at investigation was 45.2+/-12.9 years and mean disease duration at the time of investigation was 14+/-12.9 years. According to current criteria for CMT2 and dHMN, of the 10 patients who had undergone both clinical and neurophysiological examination, five were diagnosed as CMT2, two as dHMN and a further two patients were labelled as an intermediate type. Finally, due to the presence of spastic paraplegia, the index patient did not meet established criteria for the diagnosis of CMT or dHMN. DISCUSSION: Findings obtained in the present study, broadening the spectrum of clinical manifestations of disorders associated with HSP27 mutations, support the hypothesis of a continuum between CMT2 and dHMN forms and suggest a possible common spectrum between these entities and several forms of CMT plus pyramidal features (HMSN V), providing important implications for molecular genetic testing.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/diagnóstico , Proteínas de Choque Térmico HSP27/genética , Neuropatía Hereditaria Motora y Sensorial/diagnóstico , Mutación/fisiología , Adulto , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Electrofisiología/métodos , Femenino , Predisposición Genética a la Enfermedad , Neuropatía Hereditaria Motora y Sensorial/genética , Neuropatía Hereditaria Motora y Sensorial/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Paraplejía Espástica Hereditaria/genéticaRESUMEN
The aim of this study is to report the evolution of a phenotype in members of a single family carrying the heterozygous exon 1 c.178 C/G, p.Arg 60 Gly LMNA gene mutation. All mutated family members underwent neurological and cardiological assessments for a period ranging from 10 to 20 years. At onset, 4 affected adult members presented a phenotype that required pacemaker implantation. Three subjects underwent cardiac transplantation leading to long-term survival in 2 of them. One of the 3 longest surviving relatives manifested late lipodystrophy, and the other 2 had lipodystrophy, insulin-resistant diabetes, and distal peripheral neuropathy. The findings demonstrate that the exon 1 c.178 C/G, p.Arg 60 Gly LMNA gene mutation is associated with a novel phenotype featuring cardiac involvement followed by late lipodystrophy, diabetes, and peripheral axonal neuropathy.
Asunto(s)
Cardiomiopatía Dilatada/genética , ADN/genética , Familia , Lamina Tipo A/genética , Mutación , Adolescente , Adulto , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/metabolismo , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/metabolismo , Análisis Mutacional de ADN , Electromiografía , Exones , Femenino , Estudios de Seguimiento , Humanos , Lamina Tipo A/metabolismo , Lipodistrofia/diagnóstico , Lipodistrofia/genética , Lipodistrofia/metabolismo , Imagen por Resonancia Magnética , Masculino , Linaje , Fenotipo , Factores de Tiempo , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
Laminopathies are a heterogeneous group of LMNA-gene-mutation-related clinical disorders associated with alterations of cardiac and skeletal muscle and peripheral nerves, metabolic defects, and premature aging. Leg muscle imaging investigations were performed in a cohort of patients with LMNA gene alterations who were suffering from Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy type 1B, isolated cardiac disorders or a phenotype of cardiac disorders, and lipodystrophy, including one individual with peripheral neuropathy. Leg muscle imaging revealed varying degrees of alteration in the soleus and medial head of gastrocnemius in each subject. This study demonstrates that LMNA-gene-mutated patients devoid of any clinically detectable skeletal muscle involvement have the same pattern of leg muscle involvement as patients with overt skeletal muscle compromise. This finding suggests the presence of a continuum of skeletal muscle involvement among phenotypes of LMNA-gene-mutation-related skeletalmyopathy and cardiomyopathy.
Asunto(s)
Lamina Tipo A/genética , Lipodistrofia/genética , Imagen por Resonancia Magnética , Músculo Esquelético/patología , Mutación/genética , Fenotipo , Adolescente , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Lipodistrofia/diagnóstico , Masculino , Persona de Mediana Edad , Distrofia Muscular de Cinturas/diagnóstico , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Emery-Dreifuss/diagnóstico , Distrofia Muscular de Emery-Dreifuss/genética , Adulto JovenRESUMEN
Background: Gait analysis is a reliable tool to characterise ambulation in Charcot-Marie-Tooth, the obtained are complex data makes its use scarce in clinical practice. The use of synthetic measures may enable the clinician to easily interpret gait kinematics in Charcot-Marie-Tooth.Aims: To test the usefulness of Gait Profile Score as a method to quantify and monitor kinematic gait alterations in Charcot-Marie-Tooth.Methods: A group of patients with Charcot-Marie-Tooth and a control group underwent Gait Analysis. Neurological impairment was evaluated by means of the Charcot Marie Tooth neuropathy score in his original form and in the Rasch Analysis revised form. Differences in Kinematics scores induced by the pathology were assessed using the Mann-Whitney U test. The relationship between gait parameters and Charcot Marie Tooth neuropathy score was assessed by means of the Spearman correlation.Results: Twenty patients were enrolled. Mann-Whitney U test revealed a significant effect of the pathology on Gait Profile Score (p < 0.001). Charcot Marie Tooth neuropathy score was positively correlated with Gait Profile Score (Rho = 0.708, p = 0.001).Conclusion: Gait profile score can differentiate Charcot Marie Tooth from unaffected people and to quantify ambulation impairment, also identifying the joints more affected by the disease.Implications for rehabilitationPhysiotherapy and orthotics constitute the sole possible clinical approach for Charcot Marie Tooth, but the clinical scales are scarcely effective for assessing the rehabilitative outcome.Synthetic measures are able to summarize Charcot Marie tooth kinematics in a single score, and Gait Profile Score is able to differentiate patients with Charcot Marie tooth from healthy controls.Gait Profile Score is related to clinical disability as measured by the Charcot Marie tooth neuropathy score.
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Enfermedad de Charcot-Marie-Tooth , Personas con Discapacidad , Análisis de la Marcha , Marcha , Fenómenos Biomecánicos , Enfermedad de Charcot-Marie-Tooth/complicaciones , HumanosAsunto(s)
Lipodistrofia/epidemiología , Lipodistrofia/genética , Distrofias Musculares/epidemiología , Distrofias Musculares/genética , Distribución de la Grasa Corporal , Comorbilidad , Femenino , Humanos , Cariotipo , Lipodistrofia/diagnóstico , Masculino , Persona de Mediana Edad , Distrofias Musculares/diagnóstico , HermanosRESUMEN
The case of a family in which several members displayed conduction defects inherited as a dominant trait is reported. The proband was a young woman with a 1st degree atrio-ventricular block and high serum creatine kinase. Several members of the family featured cardiologic symptoms. All adult family members were clinically evaluated and blood tests including serum creatine-kinase levels, standard and Holter ECG, echocardiogram and muscle MRI were performed. LMNA gene analysis was carried out and a novel missense mutation consisting in substitution of exon 4 c.799 T/C, p.Tyr267His was revealed. The mutation was present in seven family members, five of whom displayed cardiac defects alone with no involvement of the skeletal muscle. In all mutated individuals muscle MRI featured a pattern of skeletal muscle involvement similar to that observed in autosomal dominant Emery Dreifuss muscular dystrophy, suggesting that even patients bearing a LMNA gene mutation associated to an apparently selective cardiac phenotype may present subclinical skeletal muscle involvement.
Asunto(s)
Cardiopatías/genética , Cardiopatías/patología , Lamina Tipo A/genética , Imagen por Resonancia Magnética , Mutación , Miocardio/patología , Adulto , Creatina Quinasa/sangre , Análisis Mutacional de ADN , Ecocardiografía/métodos , Electrocardiografía/métodos , Salud de la Familia , Femenino , Cardiopatías/sangre , Cardiopatías/complicaciones , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Músculo Esquelético/patología , Distrofia Muscular de Emery-Dreifuss/complicaciones , Distrofia Muscular de Emery-Dreifuss/genética , FenotipoRESUMEN
BACKGROUND: Pompe's disease is a progressive myopathy caused by mutations in the lysosomal enzyme acid alphaglucosidase gene (GAA). A wide clinical variability occurs also in patients sharing the same GAA mutations, even within the same family. METHODS: For a large series of GSDII patients we collected some clinical data as age of onset of the disease, presence or absence of muscular pain, Walton score, 6-Minute Walking Test, Vital Capacity, and Creatine Kinase. DNA was extracted and tested for GAA mutations and some genetic polymorphisms able to influence muscle properties (ACE, ACTN3, AGT and PPARα genes).We compared the polymorphisms analyzed in groups of patients with Pompe disease clustered for their homogeneous genotype. RESULTS: We have been able to identify four subgroups of patients completely homogeneous for their genotype, and two groups homogeneous as far as the second mutation is defined "very severe" or "potentially less severe". When disease free life was studied we observed a high significant difference between groups. The DD genotype in the ACE gene and the XX genotype in the ACTN3 gene were significantly associated to an earlier age of onset of the disease. The ACE DD genotype was also associated to the presence of muscle pain. CONCLUSIONS: We demonstrate that ACE and ACTN3 polymorphisms are genetic factors able to modulate the clinical phenotype of patients affected with Pompe disease.
Asunto(s)
Genotipo , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Fenotipo , Actinina/genética , Angiotensinógeno/genética , Humanos , Mutación , PPAR alfa/genética , Peptidil-Dipeptidasa A/genéticaRESUMEN
Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuropathy resulting from mutations in >30 genes expressed in either the Schwann cells or the axon of peripheral nerves. The disease is classified into demyelinating (CMT1), axonal (CMT2) or intermediate (CMTI) based on electrophysiological and pathological findings. Our study focused on the identification of a novel disease mutation in a large Sardinian family with CMT2 of autosomal dominant (AD) inheritance. All available family members were clinically evaluated and samples were collected from consenting individuals. Initially, we excluded known CMT2 genes/loci in this family. We then conducted a genome-wide linkage analysis and mapped the gene to chromosome 9q33-q34. Refined linkage and haplotype analyses defined an 11.6-Mb candidate region with a maximum LOD score of 8.06. Following exclusion of several candidate genes from the region, we targeted the LRSAM1 (leucine-rich repeat and sterile alpha motif-containing 1) gene, very recently found to be associated with autosomal recessive CMT2 in one family. For a more efficient investigation of this large gene, already available proband RNA (cDNA) was initially analyzed. Targeted DNA analysis then confirmed a novel LRSAM1 splice-site (c.2047-1G>A) mutation, causing a frameshift that introduces a stop codon three amino acids further down the new reading frame (p.Ala683ProfsX3). This mutation is located in the C-terminal RING finger motif of the encoded protein and leads to premature truncation of the protein. In the course of our work, a second LRSAM1 mutation dominantly transmitted was identified by another group. Our data further confirms that LRSAM1 mutations are associated with CMT2 of AD inheritance.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Sitios de Empalme de ARN/genética , Ubiquitina-Proteína Ligasas/genética , Axones/patología , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Mapeo Cromosómico , Cromosomas Humanos Par 9 , Femenino , Mutación del Sistema de Lectura , Ligamiento Genético , Humanos , Italia , Laminopatías , Escala de Lod , Masculino , Linaje , Polimorfismo de Nucleótido Simple , Empalme del ARNRESUMEN
The following is a report on a large family with 5 males affected by the X-linked recessive form of Emery-Dreifuss muscular dystrophy with mutation in the STA gene. A detailed longitudinal cardiological evaluation and muscle imaging studies allowed for the assessment of intrafamilial variability of cardiac and muscle involvement. Long term cardiological follow up in the 5 affected males and in 7 female carriers revealed different degrees of severity, ranging from tachycardia-bradycardia syndrome and variable biatrial and left ventricle dilatation, to an episode of isolated symptomatic sustained ventricular tachycardia requiring a device implantation. Muscle imaging in the affected males showed involvement of the soleus and medial head of gastrocnemius on leg muscles and variable involvement on thigh muscles that have not been previously reported. In some cases, imaging showed clear signs of muscle involvement even when no overt signs of weakness could be detected during clinical examination.
Asunto(s)
Corazón/fisiopatología , Músculo Esquelético/patología , Distrofia Muscular de Emery-Dreifuss/diagnóstico , Adolescente , Adulto , Femenino , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Distrofia Muscular de Emery-Dreifuss/genética , Mutación , Linaje , Adulto JovenAsunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Interferón beta/uso terapéutico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/tratamiento farmacológico , Adulto , Resistencia a Medicamentos , Femenino , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Interferon beta-1b , Conducción Nerviosa/efectos de los fármacos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/complicaciones , Enfermedades de la Tiroides/complicacionesRESUMEN
Lamins are the principal components of the nuclear lamina, a network constituting the major structural framework of the nuclear envelope. Alterations in lamin A/C have been associated with a heterogeneous series of human disorders known as laminopathies. We report the finding of a novel deletion in the central rod domain of lamin A/C exon 3 gene in four members of the same family. This genetic alteration was likely responsible for the relatively homogeneous clinical phenotype observed in our three patients, represented by a prominent cardiac conduction-system disease necessitating permanent pacemaker implantation, and limited skeletal involvement manifested by spinal rigidity and contractures. The findings from these cases further expand the clinical spectrum associated with mutations in the LMNA gene.