RESUMEN
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.
Asunto(s)
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
Anterior segment dysgenesis (ASD) comprises a wide spectrum of developmental conditions affecting the cornea, iris, and lens, which may be associated with abnormalities of other organs. To identify disease-causing variants, we performed exome sequencing in 24 South Florida families with ASD. We identified 12 likely causative variants in 10 families (42%), including single nucleotide or small insertion-deletion variants in B3GLCT, BMP4, CYP1B1, FOXC1, FOXE3, GJA1, PXDN, and TP63, and a large copy number variant involving PAX6. Four variants were novel. Each variant was detected only in one family. Likely causative variants were detected in 1 out of 7 black and 9 out of 17 white families. In conclusion, exome sequencing for ASD allows us to identify a wide spectrum of rare DNA variants in South Florida. Further studies will explore missing variants, especially in the black communities.
Asunto(s)
Anomalías del Ojo/genética , Anomalías del Ojo/patología , Marcadores Genéticos , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Niño , Anomalías del Ojo/epidemiología , Femenino , Florida/epidemiología , Humanos , Masculino , LinajeRESUMEN
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.
Asunto(s)
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
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.
