A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene

Otosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped but no genes identified. Herein, we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family. Pre-operative phenotype ranges from moderate to severe hearing loss to profound sensorineural loss requiring a cochlear implant. Mutant FOXL1 is both transcribed and translated and correctly locates to the cell nucleus. However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure. FOXL1 (rs764026385) was identified in a second unrelated case on a shared background. We conclude that FOXL1 (rs764026385) is pathogenic and causes autosomal dominant otosclerosis and propose a key inhibitory role for wildtype Foxl1 in bone remodelling in the otic capsule. New insights into the molecular pathology of otosclerosis from this study provide molecular targets for non-invasive therapeutic interventions.

Clusivity and the history of personal pronouns in East Caucasian

Personal pronouns are among the most stable lexemes in the East Caucasian family, which consists of at least forty different languages distributed over eight well established branches, with nevertheless important variations and paradigmatic reshaping across branches, languages, and even dialects. The 1st and 2nd singular pronouns have been replaced or changed shape at least once in many subparts of the family, and the main 1st person singular innovation was apparently followed by areal spread. Most languages retain two different pronouns for the 1st person plural European pronoun, but the cognates are not always clear, suggesting that although clusivity is an inherited feature of East Caucasian pronominal paradigms, its history is complex, with various types of loss and renewal. This paper attempts to draw a fine-grained and accurate picture of these 1st person plural pronouns and their history within the larger setting of personal pronouns in general. Most individual stories behind variation across branches, languages and dialects provide reasons to see inclusive pronouns as prone to be maintained or renewed over time, whereas exclusive pronouns (1st person singular or plural) are specially targeted by avoidance and replacement processes.

Familial giant cell arteritis

This is a case report of ‘familial giant cell arteritis’ in three siblings from northwest India. This is the first case report of ‘familial giant cell arteritis’ in a non-Caucasian family.

A Pathogenic Deletion in Forkhead Box L1 (FOXL1) Identifies the First Otosclerosis (OTSC) Gene

Otosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped but no genes identified. Herein, we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family. Phenotype ranges from moderate to severe hearing loss resolved by stapedectomy, to profound sensorineural loss requiring a cochlear implant. Mutant FOXL1 is both transcribed and translated and correctly locates to the cell nucleus. However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure. FOXL1 (rs764026385) was identified in a second unrelated case on a shared background. We conclude that FOXL1 (rs764026385) is pathogenic and causes autosomal dominant otosclerosis and propose a key inhibitory role for wildtype Foxl1 in bone remodelling in the otic capsule. New insights into the molecular pathology of otosclerosis from this study provide molecular targets for non-invasive therapeutic interventions.

Cwyzhy Abkhaz

In this Illustration we describe the Cwyzhy (also Tswydzhy) dialect of Abkhaz, the native language of the third author. In Cwyzhy, the language Abkhaz is called /арʰsаʃʷа/ [ˈаpʰsæʃᶣæ] аҧсашəа. Abkhaz (ISO-639-3 abk) belongs to the Northwest Caucasian family of languages, and the Abkhaz dialects are related as shown in (1) (adapted from Chirikba 2012: 36):

Myopia-26, the female-limited form of early-onset high myopia, occurring in a European family

Background Female-limited early-onset high myopia, also called Myopia-26 is a rare monogenic disorder characterized by severe short sightedness starting in early childhood and progressing to blindness potentially by the middle ages. Despite the X-linked locus of the mutated ARR3 gene, the disease paradoxically affects females only, with males being asymptomatic carriers. Previously, this disease has only been observed in Asian families and has not gone through detailed investigation concerning collateral symptoms or pathogenesis. Results We found a large Hungarian family displaying female-limited early-onset high myopia. Whole exome sequencing of two individuals identified a novel nonsense mutation (c.214C>T, p.Arg72*) in the ARR3 gene. We carried out basic ophthalmological testing for 18 family members, as well as detailed ophthalmological examination (intraocular pressure, axial length, fundus appearance, optical coherence tomography, visual field- testing) as well as colour vision- and electrophysiology tests (standard and multifocal electroretinography, pattern electroretinography and visual evoked potentials) for eight individuals. Ophthalmological examinations did not reveal any signs of cone dystrophy as opposed to animal models. Electrophysiology and colour vision tests similarly did not evidence a general cone system alteration, rather a central macular dysfunction affecting both the inner and outer (postreceptoral and receptoral) retinal structures in all patients with ARR3 mutation. Conclusions This is the first description of a Caucasian family displaying Myopia-26. We present two hypotheses that could potentially explain the pathomechanism of this disease.

Abaza and Abkhaz

This chapter surveys the phonology, morphology, and syntax of Abaza and Abkhaz, two closely related languages of the Northwest Caucasian family. These languages are strongly head-marking, expressing agreement with all core arguments and many non-core arguments, and utilizing an ergative-absolutive pattern of agreement. Typologically unusual are ‘wh-agreement’ forms corresponding to a questioned or relativized position. Verbal morphology is complex beyond this rich agreement, with directionals, applicatives, and a sizable subclass of separable verbs (i.e., those having non-contiguous roots). There is greater variation in morpheme order than often seen. The tense-mood system makes a fundamental distinction between dynamic verbs and stative predicates (nouns, postpositions, and certain lexically specified verbs), with more tense options in the dynamic system. Another distinction which cuts across predicates of both types is that between indicative and non-indicative tenses (traditionally ‘finite’ and ‘non-finite,’ though not satisfying the usual diagnostics for finiteness). Negation is expressed by verbal affixes, but in various configurations depending on factors such as tense and mood. Syntactically, these languages are basically head-final (SOV), though with variation allowed based on pragmatic functions. Typologically significant is the pervasive use of relativized forms (pseudo-clefting) and converbs. Abaza and Abkhaz are known for their large consonant inventories, enriched by ejectives, palatalization, and labialization, as well as uvular and pharyngeal places of articulation, and contrasting with a minimal two-vowel system.

Lak

This chapter gives a grammatical overview of the Kumukh dialect of Lak, which is the basis of the Lak standard language, which is one of the offical languages of the Republic of Daghestan in the Russian Federation. Lak is a member of the Dagestanian branch of the Nakh-Daghestanian (Northeast) Caucasian family and is spoken by close to 200,000 people, mostly in the central highlands of Daghestan. Topics of interest covered in this chapter include glottalization and gemination in stops and affricates, pharyngealized vowels, agglutination, exuberant gender agreement, Lak’s complex tense-aspect-mood-evidential system, ergative and biabsolutive agreement patterns, and long-distance anaphora wherein a reflexive in a subordinate clause can refer to the absolutive or ergative (= genitive) subject of the main clause. Among Daghestanian languages, Lak is also remarkable for the fact that its dialectal differentiation is not as strong as in other Daghestanian branches, especially its closest relative, Dargwa.

Myopia-26, the female-limited form of early-onset high myopia, occurring in a European family

Background: Female-limited early-onset high myopia, also called Myopia-26 is a rare monogenic disorder characterized by severe short sightedness starting in early childhood and progressing to blindness potentially by the middle ages. Despite the X-linked locus of the mutated ARR3 gene, the disease paradoxically affects females only, with males being asymptomatic carriers. Previously, this disease has only been observed in Asian families and has not gone through detailed investigation concerning collateral symptoms or pathogenesis Results: We found a large Hungarian family displaying female-limited early-onset high myopia. Whole exome sequencing of two individuals identified a novel nonsense mutation (c.214C>T, p.Arg72*) in the ARR3 gene. We carried out basic ophthalmological testing for 18 family members, as well as detailed ophthalmological examination (intraocular pressure, axial length, fundus appearance, optical coherence tomography, visual field- testing) as well as colour vision- and electrophysiology tests (standard and multifocal electroretinography, pattern electroretinography and visual evoked potentials) for eight individuals. Ophthalmological examinations did not reveal any signs of cone dystrophy as opposed to animal models. Electrophysiology and colour vision tests similarly did not evidence a general cone system alteration, rather a central macular dysfunction affecting both the inner and outer (postreceptoral and receptoral) retinal structures in all patients with ARR3 mutation. Conclusions: This is the first description of a Caucasian family displaying Myopia-26. We present two hypotheses that could potentially explain the pathomechanism of this disease.

Myopia-26, the female-limited form of early-onset high myopia, occurring in a European family

Background: Female-limited early-onset high myopia, also called Myopia-26 is a rare monogenic disorder characterized by severe short sightedness starting in early childhood and progressing to blindness potentially by the middle ages. Despite the X-linked locus of the mutated ARR3 gene, the disease paradoxically affects females only, with males being asymptomatic carriers. Previously, this disease has only been observed in Asian families and has not gone through detailed investigation concerning collateral symptoms or pathogenesisResults: We found a large Hungarian family displaying female-limited early-onset high myopia. Whole exome sequencing of two individuals identified a novel nonsense mutation (c.214C>T, p.Arg72*) in the ARR3 gene. We carried out basic ophthalmological testing for 18 family members, as well as detailed ophthalmological examination (intraocular pressure, axial length, fundus appearance, optical coherence tomography, visual field- testing) as well as colour vision- and electrophysiology tests (standard and multifocal electroretinography, pattern electroretinography and visual evoked potentials) for eight individuals. Ophthalmological examinations did not reveal any signs of cone dystrophy as opposed to animal models. Electrophysiology and colour vision tests similarly did not evidence a general cone system alteration, rather a central macular dysfunction affecting both the inner and outer (postreceptoral and receptoral) retinal structures in all patients with ARR3 mutation. Conclusions: This is the first description of a Caucasian family displaying Myopia-26. We present two hypotheses that could potentially explain the pathomechanism of this disease.