Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families

Distinct patterns of brain activity characterise lexical activation and competition in spoken word production

Contains fulltext : 126491.pdf (publisher's version ) (Open Access)According to a prominent theory of language production, concepts activate multiple associated words in memory, which enter into competition for selection. However, only a few electrophysiological studies have identified brain responses reflecting competition. Here, we report a magnetoencephalography study in which the activation of competing words was manipulated by presenting pictures (e.g., dog) with distractor words. The distractor and picture name were semantically related (cat), unrelated (pin), or identical (dog). Related distractors are stronger competitors to the picture name because they receive additional activation from the picture relative to other distractors. Picture naming times were longer with related than unrelated and identical distractors. Phase-locked and non-phase-locked activity were distinct but temporally related. Phase-locked activity in left temporal cortex, peaking at 400 ms, was larger on unrelated than related and identical trials, suggesting differential activation of alternative words by the picture-word stimuli. Non-phase-locked activity between roughly 350-650 ms (4-10 Hz) in left superior frontal gyrus was larger on related than unrelated and identical trials, suggesting differential resolution of the competition among the alternatives, as reflected in the naming times. These findings characterise distinct patterns of activity associated with lexical activation and competition, supporting the theory that words are selected by competition.11 p

Distractor strength and selective attention in picture-naming performance

Contains fulltext : 102442pub.pdf (publisher's version ) (Open Access)Whereas it has long been assumed that competition plays a role in lexical selection in word production (e.g., Levelt, Roelofs, & Meyer, 1999), recently Finkbeiner and Caramazza (2006) argued against the competition assumption on the basis of their observation that visible distractors yield semantic interference in picture naming, whereas masked distractors yield semantic facilitation. We examined an alternative account of these findings that preserves the competition assumption. According to this account, the interference and facilitation effects of distractor words reflect whether or not distractors are strong enough to exceed a threshold for entering the competition process. We report two experiments in which distractor strength was manipulated by means of coactivation and visibility. Naming performance was assessed in terms of mean response time (RT) and RT distributions. In Experiment 1, with low coactivation, semantic facilitation was obtained from clearly visible distractors, whereas poorly visible distractors yielded no semantic effect. In Experiment 2, with high coactivation, semantic interference was obtained from both clearly and poorly visible distractors. These findings support the competition threshold account of the polarity of semantic effects in naming.14 p