RESUMEN
Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect â¼10 000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated a Sord knockout (KO), Sord-/-, Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioural tests as well as biochemical, physiological and comprehensive histological examinations. Sord-/- rats had remarkably increased levels of sorbitol in serum, CSF and peripheral nerve. Moreover, serum from Sord-/- rats contained significantly increased levels of neurofilament light chain, an established biomarker for axonal degeneration. Motor performance significantly declined in Sord-/- animals starting at â¼7 months of age. Gait analysis evaluated with video motion-tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de- and remyelinated axons, and a likely pathognomonic finding-enlarged 'ballooned' myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary, Sord-/- rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy.
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Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Animales , Ratas , Sorbitol/metabolismo , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Enfermedades del Sistema Nervioso Periférico/patología , Enfermedades del Sistema Nervioso Periférico/genética , L-Iditol 2-Deshidrogenasa/deficiencia , L-Iditol 2-Deshidrogenasa/metabolismo , Masculino , Femenino , Conducción NerviosaRESUMEN
Congenital hearing loss is the most common birth defect, estimated to affect 2-3 in every 1000 births, with ~50-60% of those related to genetic causes. Technological advances enabled the identification of hundreds of genes related to hearing loss (HL), with important implications for patients, their families, and the community. Despite these advances, in Latin America, the population with hearing loss remains underdiagnosed, with most studies focusing on a single locus encompassing the GJB2/GJB6 genes. Here we discuss how current and emerging genetic knowledge has the potential to alter the approach to diagnosis and management of hearing loss, which is the current situation in Latin America, and the barriers that still need to be overcome.
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Sordera , Pérdida Auditiva , Humanos , Conexinas/genética , Conexina 26/genética , Mutación , América Latina/epidemiología , Pruebas Genéticas , Pérdida Auditiva/diagnóstico , Pérdida Auditiva/genética , Sordera/diagnóstico , Sordera/genéticaRESUMEN
Hearing loss (HL) is a heterogenous trait with pathogenic variants in more than 200 genes that have been discovered in studies involving small and large HL families. Over one-third of families with hereditary HL remain etiologically undiagnosed after screening for mutations in the recognized genes. Genetic heterogeneity complicates the analysis in multiplex families where variants in more than one gene can be causal in different individuals even in the same sibship. We employed exome or genome sequencing in at least two affected individuals with congenital or prelingual-onset, severe to profound, non-syndromic, bilateral sensorineural HL from four multiplex families. Bioinformatic analysis was performed to identify variants in known and candidate deafness genes. Our results show that in these four families, variants in a single HL gene do not explain HL in all affected family members, and variants in another known or candidate HL gene were detected to clarify HL in the entire family. We also present a variant in TOGARAM2 as a potential cause underlying autosomal recessive non-syndromic HL by showing its presence in a family with HL, its expression in the cochlea and the localization of the protein to cochlear hair cells. Conclusively, analyzing all affected family members separately can serve as a good source for the identification of variants in known and novel candidate genes for HL.
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Heterogeneidad Genética , Linaje , Adulto , Femenino , Humanos , Masculino , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/patología , Mutación , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismoRESUMEN
Geleophysic dysplasia-1 (GD1) is an autosomal recessive disorder caused by ADAMTS-like 2 (ADAMTSL2) variants. It is characterized by distinctive facial features, limited joint mobility, short stature, brachydactyly, and life-threatening cardiorespiratory complications. The clinical spectrum spans from perinatal lethality to milder adult phenotypes. We developed and characterized cellular and mouse models, to replicate the genetic profile of a patient who is compound heterozygous for 2 ADAMTSL2 variants, namely p.R61H and p.A165T. The impairment of ADAMTSL2 secretion was observed in both variants, but p.A165T exhibited a more severe impact. Mice carrying different allelic combinations revealed a spectrum of phenotypic severity, from lethality in knockout homozygotes to mild growth impairment observed in adult p.R61H homozygotes. Homozygous and hemizygous p.A165T mice survived but displayed severe respiratory and cardiac dysfunction. The respiratory dysfunction mainly affected the expiration phase, and some of these animals had microscopic post-obstructive pneumonia. Echocardiograms and MRI studies revealed a significant systolic dysfunction, accompanied by a reduction of the aortic root size. Histology verified the presence of hypertrophic cardiomyopathy with myocyte hypertrophy, chondroid metaplasia, and mild interstitial fibrosis. This study revealed a substantial correlation between the degree of impaired ADAMTSL2 secretion and the severity of the observed phenotype in GD1.
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Proteínas ADAMTS , Enfermedades del Desarrollo Óseo , Deformidades Congénitas de las Extremidades , Adulto , Humanos , Animales , Ratones , Proteínas ADAMTS/genética , Enfermedades del Desarrollo Óseo/genética , Mutación , FenotipoRESUMEN
GATAD2B (GATA zinc finger domain containing 2B) variants are associated with the neurodevelopmental syndrome GAND, characterized by intellectual disability (ID), infantile hypotonia, apraxia of speech, epilepsy, macrocephaly and distinct facial features. GATAD2B encodes for a subunit of the Nucleosome Remodeling and Histone Deacetylase (NuRD) complex. NuRD controls transcriptional programs critical for proper neurodevelopment by coupling histone deacetylase with ATP-dependent chromatin remodeling activity. To study mechanisms of pathogenesis for GAND, we characterized a mouse model harboring an inactivating mutation in Gatad2b. Homozygous Gatad2b mutants die perinatally, while haploinsufficient Gatad2b mice exhibit behavioral abnormalities resembling the clinical features of GAND patients. We also observed abnormal cortical patterning, and cellular proportions and cell-specific alterations in the developmental transcriptome in these mice. scRNAseq of embryonic cortex indicated misexpression of genes key for corticogenesis and associated with neurodevelopmental syndromes such as Bcl11b, Nfia and H3f3b and Sox5. These data suggest a crucial role for Gatad2b in brain development.
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Discapacidad Intelectual , Proteínas Represoras , Humanos , Animales , Ratones , Factores de Transcripción GATA/genética , Discapacidad Intelectual/genética , Discapacidad Intelectual/complicaciones , Factores de Transcripción/genética , Histona Desacetilasas , Síndrome , Proteínas Supresoras de TumorRESUMEN
Biallelic SORD mutations cause one of the most frequent forms of recessive hereditary neuropathy, estimated to affect approximately 10,000 patients in North America and Europe alone. Pathogenic SORD loss-of-function changes in the encoded enzyme sorbitol dehydrogenase result in abnormally high sorbitol levels in cells and serum. How sorbitol accumulation leads to peripheral neuropathy remains to be elucidated. A reproducible animal model for SORD neuropathy is essential to illuminate the pathogenesis of SORD deficiency and for preclinical studies of potential therapies. Therefore, we have generated a Sord knockout (KO), Sord -/- , Sprague Dawley rat, to model the human disease and to investigate the pathophysiology underlying SORD deficiency. We have characterized the phenotype in these rats with a battery of behavioral tests as well as biochemical, physiological, and comprehensive histological examinations. Sord -/- rats had remarkably increased levels of sorbitol in serum, cerebral spinal fluid (CSF), and peripheral nerve. Moreover, serum from Sord -/- rats contained significantly increased levels of neurofilament light chain, NfL, an established biomarker for axonal degeneration. Motor performance significantly declined in Sord -/- animals starting at â¼7 months of age. Gait analysis evaluated with video motion tracking confirmed abnormal gait patterns in the hindlimbs. Motor nerve conduction velocities of the tibial nerves were slowed. Light and electron microscopy of the peripheral nervous system revealed degenerating myelinated axons, de- and remyelinated axons, and a likely pathognomonic finding - enlarged "ballooned" myelin sheaths. These findings mainly affected myelinated motor axons; myelinated sensory axons were largely spared. In summary, Sord -/- rats develop a motor-predominant neuropathy that closely resembles the human phenotype. Our studies revealed novel significant aspects of SORD deficiency, and this model will lead to an improved understanding of the pathophysiology and the therapeutic options for SORD neuropathy.
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Discovery of deafness genes and elucidating their functions have substantially contributed to our understanding of hearing physiology and its pathologies. Here we report on DNA variants in MINAR2, encoding membrane integral NOTCH2-associated receptor 2, in four families underlying autosomal recessive nonsyndromic deafness. Neurologic evaluation of affected individuals at ages ranging from 4 to 80 y old does not show additional abnormalities. MINAR2 is a recently annotated gene with limited functional understanding. We detected three MINAR2 variants, c.144G > A (p.Trp48*), c.412_419delCGGTTTTG (p.Arg138Valfs*10), and c.393G > T, in 13 individuals with congenital- or prelingual-onset severe-to-profound sensorineural hearing loss (HL). The c.393G > T variant is shown to disrupt a splice donor site. We show that Minar2 is expressed in the mouse inner ear, with the protein localizing mainly in the hair cells, spiral ganglia, the spiral limbus, and the stria vascularis. Mice with loss of function of the Minar2 protein (Minar2tm1b/tm1b) present with rapidly progressive sensorineural HL associated with a reduction in outer hair cell stereocilia in the shortest row and degeneration of hair cells at a later age. We conclude that MINAR2 is essential for hearing in humans and mice and its disruption leads to sensorineural HL. Progressive HL observed in mice and in some affected individuals and as well as relative preservation of hair cells provides an opportunity to interfere with HL using genetic therapies.
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Pérdida Auditiva Sensorineural , Receptor Notch2 , Receptores de Superficie Celular , Animales , Pérdida Auditiva Sensorineural/genética , Humanos , Mutación con Pérdida de Función , Ratones , Receptor Notch2/genética , Receptor Notch2/metabolismo , Receptores de Superficie Celular/genética , Estereocilios/metabolismoRESUMEN
Purpose: The Precision Medicine Health Disparities Collaborative fosters collaboration between researchers with diverse backgrounds in precision medicine and health disparities research, to include training at the interface between genomics and health disparities. Understanding how perceptions about precision medicine differ by background may inform activities to better understand such differences. Methods: We conducted a cross-sectional survey of Center members and beyond. Data were collected on categories of educational background, current activities, and level of agreement with 20 statements related to genomics and health disparities. Respondents categorized their background and activities as social/behavioral, genetics, both, or neither. Fisher's exact test was used to assess levels of agreement in response to each statement. Statistically significant associations were further analyzed using ordinal logistic regression adjusting for age, self-identified race/ethnicity, and gender. Results: Of 130 respondents, 50 (38%) identified educational backgrounds and current activities as social-behavioral or genomic 55 (42%). Respondents differed by educational background on the statement Lifestyle and other life experiences influence how genes impact disease risk (p=0.0009). Respondents also differed by current activities on the statement Reducing disparities in access to health care will make precision medicine more effective (p=0.0008), and on Racism and discrimination make me concerned about how genetic test results will be used (p=0.0011). Conclusions: Respondents who differed on prior education and current activities, whether social behavioral science or human genomics, were associated with different perceptions regarding precision medicine and health disparities. These results identify potential barriers and opportunities to strengthen transdisciplinary collaboration.
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P2RX2 encodes the P2X2 receptor, which is an adenosine triphosphate (ATP) gated (purinoreceptor) ion channel. P2RX2 c. 178G > T (p.V60L) mutation was previously identified in two unrelated Chinese families, as the cause of human DFNA41, a form of dominant, early-onset and progressive sensorineural hearing loss. We generated and characterized a knock-in mouse model based on human p.V60L mutation that recapitulates the human phenotype. Heterozygous KI mice started to exhibit hearing loss at 21-day-old and progressed to deafness by 6-month-old. Vestibular dysfunction was also observed in mutant mice. Abnormal morphology of the inner hair cells and ribbon synapses was progressively observed in KI animals suggesting that P2rx2 plays a role in the membrane spatial location of the ribbon synapses. These results suggest that P2rx2 is essential for acoustic information transfer, which can be the molecular mechanism related to hearing loss.
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Pérdida Auditiva Sensorineural/genética , Receptores Purinérgicos P2X2/genética , Adenosina Trifosfato/metabolismo , Animales , Modelos Animales de Enfermedad , Técnicas de Sustitución del Gen , Células Ciliadas Auditivas Internas/patología , Pérdida Auditiva Sensorineural/patología , Heterocigoto , Humanos , Ratones , Mutación/genética , Linaje , Fenotipo , Sinapsis/genética , Sinapsis/patología , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/patologíaRESUMEN
Hair cells (HCs) play crucial roles in perceiving sound, acceleration, and fluid motion. The tonotopic architecture of the sensory epithelium recognizes mechanical stimuli and convert them into electrical signals. The expression and regulation of the genes in the inner ear is very important to keep the sensory organ functional. Our study is the first to investigate the role of the epigenetic reader Brd4 in the mouse inner ear. We demonstrate that HC specific deletion of Brd4 in vivo in the mouse inner ear is sufficient to cause profound hearing loss (HL), degeneration of stereocilia, nerve fibers and HC loss postnatally in mouse; suggesting an important role in hearing function and maintenance.
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Molecular mechanisms governing the development of the mammalian cochlea, the hearing organ, remain largely unknown. Through genome sequencing in 3 subjects from 2 families with nonsyndromic cochlear aplasia, we identified homozygous 221-kb and 338-kb deletions in a noncoding region on chromosome 8 with an approximately 200-kb overlapping section. Genomic location of the overlapping deleted region started from approximately 350 kb downstream of GDF6, which codes for growth and differentiation factor 6. Otic lineage cells differentiated from induced pluripotent stem cells derived from an affected individual showed reduced expression of GDF6 compared with control cells. Knockout of Gdf6 in a mouse model resulted in cochlear aplasia, closely resembling the human phenotype. We conclude that GDF6 plays a necessary role in early cochlear development controlled by cis-regulatory elements located within an approximately 500-kb region of the genome in humans and that its disruption leads to deafness due to cochlear aplasia.
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Cromosomas Humanos Par 8 , Cóclea , Enfermedades Cocleares , Factor 6 de Diferenciación de Crecimiento , Elementos de Respuesta , Animales , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 8/metabolismo , Cóclea/embriología , Cóclea/patología , Enfermedades Cocleares/embriología , Enfermedades Cocleares/genética , Enfermedades Cocleares/patología , Femenino , Factor 6 de Diferenciación de Crecimiento/biosíntesis , Factor 6 de Diferenciación de Crecimiento/genética , Humanos , Masculino , Ratones , Ratones TransgénicosRESUMEN
Potocki-Lupski syndrome (PTLS) is a genetic disorder that results from an interstitial duplication within chromosome 17p11.2. Children with PTLS typically present with infantile hypotonia, failure to thrive, and global developmental delay with or without major organ system involvement. Systematic clinical studies regarding growth, cardiovascular disease, and neurocognitive profiles have been published; however, systematic evaluation of central nervous system structure by magnetic resonance imaging (MRI) of the brain has not been reported. Herein, we describe three patients with PTLS who were found-in the course of routine clinical care-to have a type 1 Arnold-Chiari malformation (CM-1). This finding raises the question of whether the incidence of CM-1 is increased in PTLS, and hence, if an MRI of the brain should be considered in the evaluation of all patients with this chromosomal duplication syndrome.
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Anomalías Múltiples/genética , Malformación de Arnold-Chiari/genética , Trastornos de los Cromosomas/genética , Duplicación Cromosómica/genética , Femenino , Humanos , LactanteRESUMEN
We have identified a GRAP variant (c.311A>T; p.Gln104Leu) cosegregating with autosomal recessive nonsyndromic deafness in two unrelated families. GRAP encodes a member of the highly conserved growth factor receptor-bound protein 2 (GRB2)/Sem-5/drk family of proteins, which are involved in Ras signaling; however, the function of the growth factor receptor-bound protein 2 (GRB2)-related adaptor protein (GRAP) in the auditory system is not known. Here, we show that, in mouse, Grap is expressed in the inner ear and the protein localizes to the neuronal fibers innervating cochlear and utricular auditory hair cells. Downstream of receptor kinase (drk), the Drosophila homolog of human GRAP, is expressed in Johnston's organ (JO), the fly hearing organ, and the loss of drk in JO causes scolopidium abnormalities. drk mutant flies present deficits in negative geotaxis behavior, which can be suppressed by human wild-type but not mutant GRAP. Furthermore, drk specifically colocalizes with synapsin at synapses, suggesting a potential role of such adaptor proteins in regulating actin cytoskeleton dynamics in the nervous system. Our findings establish a causative link between GRAP mutation and nonsyndromic deafness and suggest a function of GRAP/drk in hearing.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteína Adaptadora GRB2/metabolismo , Pérdida Auditiva Sensorineural/metabolismo , Secuencia de Aminoácidos , Animales , Proteínas Portadoras/metabolismo , Sordera/microbiología , Drosophila/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Unión Proteica/fisiología , Transducción de Señal/fisiologíaRESUMEN
Myosin light chain 2 ( MYL2) gene encodes the myosin regulatory light chain (RLC) simultaneously in heart ventricles and in slow-twitch skeletal muscle. Using transgenic mice with cardiac-specific expression of the human R58Q-RLC mutant, we sought to determine whether the hypertrophic cardiomyopathy phenotype observed in papillary muscles (PMs) of R58Q mice is also manifested in slow-twitch soleus (SOL) muscles. Skinned SOL muscles and ventricular PMs of R58Q animals exhibited lower contractile force that was not observed in the fast-twitch extensor digitorum longus muscles of R58Q vs. wild-type-RLC mice, but mutant animals did not display gross muscle weakness in vivo. Consistent with SOL muscle abnormalities in R58Q vs. wild-type mice, myosin ATPase staining revealed a decreased proportion of fiber type I/type II only in SOL muscles but not in the extensor digitorum longus muscles. The similarities between SOL muscles and PMs of R58Q mice were further supported by quantitative proteomics. Differential regulation of proteins involved in energy metabolism, cell-cell interactions, and protein-protein signaling was concurrently observed in the hearts and SOL muscles of R58Q mice. In summary, even though R58Q expression was restricted to the heart of mice, functional similarities were clearly observed between the hearts and slow-twitch skeletal muscle, suggesting that MYL2 mutated models of hypertrophic cardiomyopathy may be useful research tools to study the molecular, structural, and energetic mechanisms of cardioskeletal myopathy associated with myosin RLC.-Kazmierczak, K., Liang, J., Yuan, C.-C., Yadav, S., Sitbon, Y. H., Walz, K., Ma, W., Irving, T. C., Cheah, J. X., Gomes, A. V., Szczesna-Cordary, D. Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain.
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Miosinas Cardíacas/genética , Miosinas Cardíacas/fisiología , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/fisiopatología , Fibras Musculares de Contracción Lenta/fisiología , Cadenas Ligeras de Miosina/genética , Cadenas Ligeras de Miosina/fisiología , Sustitución de Aminoácidos , Animales , Cardiomiopatía Hipertrófica/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Mutantes , Ratones Transgénicos , Contracción Muscular/genética , Contracción Muscular/fisiología , Fibras Musculares de Contracción Lenta/patología , Mutación Missense , Contracción Miocárdica/genética , Contracción Miocárdica/fisiología , Miocardio/metabolismo , Miocardio/patología , Músculos Papilares/patología , Músculos Papilares/fisiopatología , ProteómicaRESUMEN
Molecular mechanisms governing the development of the human cochlea remain largely unknown. Through genome sequencing, we identified a homozygous FOXF2 variant c.325A>T (p.I109F) in a child with profound sensorineural hearing loss (SNHL) associated with incomplete partition type I anomaly of the cochlea. This variant is not found in public databases or in over 1000 ethnicity-matched control individuals. I109 is a highly conserved residue in the forkhead box (Fox) domain of FOXF2, a member of the Fox protein family of transcription factors that regulate the expression of genes involved in embryogenic development as well as adult life. Our in vitro studies show that the half-life of mutant FOXF2 is reduced compared to that of wild type. Foxf2 is expressed in the cochlea of developing and adult mice. The mouse knockout of Foxf2 shows shortened and malformed cochleae, in addition to altered shape of hair cells with innervation and planar cell polarity defects. Expressions of Eya1 and Pax3, genes essential for cochlear development, are reduced in the cochleae of Foxf2 knockout mice. We conclude that FOXF2 plays a major role in cochlear development and its dysfunction leads to SNHL and developmental anomalies of the cochlea in humans and mice.
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Cóclea/embriología , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/fisiología , Adulto , Animales , Niño , Cóclea/metabolismo , Cóclea/fisiología , Desarrollo Embrionario , Femenino , Células Ciliadas Auditivas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Organogénesis , Factor de Transcripción PAX3/genética , Factor de Transcripción PAX3/fisiología , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas/fisiología , Transducción de Señal/genética , Secuenciación Completa del GenomaRESUMEN
RIPOR2 (previously known as FAM65B) localizes to stereocilia of auditory hair cells and causes deafness when its function is disturbed by mutations. Here, we demonstrate that during the morphogenesis of the hair cell bundle, absence of Ripor2 affects the orientation of this key subcellular structure. We show that Ripor2 interacts with Myh9, a protein encoded by a known deafness gene. Absence of Ripor2 is associated with low Myh9 abundance in the mouse cochlea despite increased amount of Myh9 transcripts. While Myh9 is mainly expressed in stereocilia, a phosphorylated form of Myh9 is particularly enriched in the kinocilium. In Ripor2-deficient mice, kinocilium shows an aberrant localization which associates with a reduced content of phosphorylated Myh9. Acetylated alpha tubulin, another specific kinociliary protein which contributes to microtubule stabilization, is reduced in the absence of Ripor2 as well. We propose that Ripor2 deficiency influences abundance and/or post-translational modifications of proteins expressed in both stereocilia and kinocilia. This effect may have a negative impact on the structure and function of the auditory hair cell bundle.
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Proteínas Portadoras/fisiología , Células Ciliadas Auditivas/fisiología , Proteínas de la Membrana/fisiología , Miosina Tipo IIA no Muscular/fisiología , Animales , Moléculas de Adhesión Celular , Cilios/fisiología , Oído Interno/fisiología , Epitelio/fisiología , Células HEK293 , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Cadenas Pesadas de Miosina , ARN Mensajero/metabolismoRESUMEN
While recent studies have revealed a substantial portion of the genes underlying human hearing loss, the extensive genetic landscape has not been completely explored. Here, we report a loss-of-function variant (c.72delA) in MPZL2 in three unrelated multiplex families from Turkey and Iran with autosomal recessive nonsyndromic hearing loss. The variant co-segregates with moderate sensorineural hearing loss in all three families. We show a shared haplotype flanking the variant in our families implicating a single founder. While rare in other populations, the allele frequency of the variant is ~ 0.004 in Ashkenazi Jews, suggesting that it may be an important cause of moderate hearing loss in that population. We show that Mpzl2 is expressed in mouse inner ear, and the protein localizes in the auditory inner and outer hair cells, with an asymmetric subcellular localization. We thus present MPZL2 as a novel gene associated with sensorineural hearing loss.
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Moléculas de Adhesión Celular/genética , Sordera/genética , Células Ciliadas Auditivas Internas/metabolismo , Pérdida Auditiva Sensorineural/genética , Animales , Sordera/fisiopatología , Oído Interno/crecimiento & desarrollo , Oído Interno/fisiopatología , Femenino , Frecuencia de los Genes , Genes Recesivos , Células Ciliadas Auditivas Internas/patología , Haplotipos/genética , Pérdida Auditiva Sensorineural/fisiopatología , Humanos , Irán/epidemiología , Judíos/genética , Masculino , Ratones , Mutación , Linaje , Células de Schwann/patología , TurquíaRESUMEN
Deletions and mutations involving the Retinoic Acid Induced 1 (RAI1) gene at 17p11.2 cause Smith-Magenis syndrome (SMS). Here we report a patient with autism as the main clinical presentation, with some SMS-like features and a rare de novo RAI1 gene mutation, c.3440G > A (p.R1147Q). We functionally characterized the RAI1 p.R1147Q mutant protein. The mutation, located near the nuclear localization signal, had no effect on the subcellular localization of the mutant protein. However, similar to previously reported RAI1 missense mutations in SMS patients, the RAI1 p.R1147Q mutant protein showed a significant deficiency in activating in vivo transcription of a reporter gene driven by a BDNF (brain-derived neurotrophic factor) intronic enhancer. In addition, expression of other genes associated with neurobehavioral abnormalities and/or neurodevelopmental disorders were found to be altered in this patient. These results suggest a likely contribution of RAI1, either alone or in combination of other factors, to social behavior and reinforce the RAI1 gene as a candidate gene in patients with autistic manifestations or social behavioral abnormalities.
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Background: Autism is characterized by difficulties in social interaction, communication, and repetitive behaviors; with different degrees of severity in each of the core areas. Haploinsufficiency and point mutations of RAI1 are associated with Smith-Magenis syndrome (SMS), a genetic condition that scores within the autism spectrum range for social responsiveness and communication, and is characterized by neurobehavioral abnormalities, intellectual disability, developmental delay, sleep disturbance, and self-injurious behaviors. Methods: To investigate the relationship between Rai1 and social impairment, we evaluated the Rai1+/- mice with a battery of tests to address social behavior in mice. Results: We found that the mutant mice showed diminished interest in social odors, abnormal submissive tendencies, and increased repetitive behaviors when compared to wild type littermates. Conclusions: These findings suggest that Rai1 contributes to social behavior in mice, and prompt it as a candidate gene for the social behaviors observed in Smith-Magenis Syndrome patients.
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Hair cells of the inner ear, the mechanosensory receptors, convert sound waves into neural signals that are passed to the brain via the auditory nerve. Little is known about the molecular mechanisms that govern the development of hair cell-neuronal connections. We ascertained a family with autosomal recessive deafness associated with a common cavity inner ear malformation and auditory neuropathy. Via whole-exome sequencing, we identified a variant (c.2207G>C, p.R736T) in ROR1 (receptor tyrosine kinase-like orphan receptor 1), cosegregating with deafness in the family and absent in ethnicity-matched controls. ROR1 is a tyrosine kinase-like receptor localized at the plasma membrane. At the cellular level, the mutation prevents the protein from reaching the cellular membrane. In the presence of WNT5A, a known ROR1 ligand, the mutated ROR1 fails to activate NF-κB. Ror1 is expressed in the inner ear during development at embryonic and postnatal stages. We demonstrate that Ror1 mutant mice are severely deaf, with preserved otoacoustic emissions. Anatomically, mutant mice display malformed cochleae. Axons of spiral ganglion neurons show fasciculation defects. Type I neurons show impaired synapses with inner hair cells, and type II neurons display aberrant projections through the cochlear sensory epithelium. We conclude that Ror1 is crucial for spiral ganglion neurons to innervate auditory hair cells. Impairment of ROR1 function largely affects development of the inner ear and hearing in humans and mice.