A hypomorphic mutation in lpin1 induces progressively improving peripheral neuropathy in the rat

The Lpin1 gene encodes the phosphatidate phosphatase (PAP1) enzyme Lipin 1, which plays a critical role in lipid metabolism. In this study we describe the identification and characterization of a rat with a mutated Lpin1 gene (Lpin11Hubr ), generated by N-ethyl-N-nitrosourea mutagenesis. Lpin11Hubr rats are characterized by hindlimb paralysis that is detectable from the second postnatal week. Sequencing of Lpin1 identified a missense mutation in the 5'-end splice site of exon 18 resulting in mis-splicing, a reading frame shift and a premature stop codon. As this mutation does not induce nonsense-mediated decay, it allows the production of a truncated Lipin 1 protein lacking PAP1 activity. As a consequence, Lpin11Hubr rats develop hypomyelination rather than the pronounced demyelination defect characteristic of Lpin1fld/fld mice, which carry a null allele for Lpin1. Furthermore, histological and molecular analyses revealed that this lesion improve in older Lpin11Hubr rats as compared to young Lpin11Hubr rats and Lpin1fld/fld mice. The observed differences between the murine Lpin1fld/fld mutant, with a complete loss of Lipin 1 function, and the Lpin1Hubr rat, with a truncated PAP1 activitydeficient form of Lipin 1, provide additional evidence for suggested non-enzymatic Lipin1 function residing outside of its PAP1 domain. While we are cautious in making a direct parallel between the presented rodent model and human disease, our data may provide new insight into pathogenicity of recently identified human Lpin1 mutations. *These authors contributed equally.

Bilateral anterior ischemic optic neuropathy following influenza vaccination.

Optic neuritis is an occasional complication of vaccination. Visual loss can be unilateral or bilateral, and most patients recover substantially without treatment. The presumptive mechanism is an immune-mediated demyelinating injury of the optic nerve. We report two patients who had permanent visual loss following influenza vaccination. Their pattern of visual loss, segmental optic disc changes, and failure of visual recovery were atypical for demyelinating optic neuritis and reminiscent of a primary ischemic injury to the optic nerve. We speculate that an immune complex-mediated vasculopathy following vaccination can cause anterior ischemic optic neuropathy. Clinicians should be aware of this entity because of the less favorable prognosis for visual recovery in these cases.

Clinical and electrophysiological recovery in Leber hereditary optic neuropathy with G3460A mutation.

To report a case of clinical and electrophysiological recovery in Leber hereditary optic neuropathy (LHON) with G3460A Mutation. A 10-year-old boy with a three-month history of painless bilateral sequential visual loss upon presentation underwent visual acuity (diminished), anterior and posterior segment examination (normal), fluorescein angiography (normal), Goldman kinetic perimetry (bilateral central scotomata), genetic (a point G3460A mutation) and electrophysiological investigation (undetectable pattern visual evoked potentials (VEP); low amplitude, broadened and reduced flash VEPs and loss of the N95 component in the pattern electroretinograms). Diagnosis of LHON was made. Eighteen months later vision and electrophysiological tests results began spontaneously improving. Kinetic perimetry revealed reduced density and size of scotomata. Two years later, there had been further electrophysiological improvement. This report describes both clinical and electrophysiological improvement in LHON with G3460A mutation.

Phenotypic and molecular characterization of the onset of neuropathy in rodent models of diabetes mellitus

Abstract : The principal focus of this work was to study the molecular changes leading to the development of diabetic peripheral neuropathy (DPN). DPN is the most common complication associated with both type I and II diabetes mellitus (DM). This pathology is the leading cause of non-traumatic amputations. Even though the pathological and morphological changes underlying DPN are relatively well described, the implicated molecular mechanisms remain poorly understood. The following two approaches were developed to study the development of DPN in a rodent model of DM type I. As a first approach, we studied the implication of lipid metabolism in DPN phenotype, concentrating on Sterol Response Element Binding Protein (SREBP)-lc which is the key regulator of storage lipid metabolism. We showed that SREBP-1c was expressed in peripheral nerves and that its expression profile followed the expression of genes involved in storage lipid metabolism. In addition, the expression of SREBP-1c in the endoneurium of peripheral nerves was dependant upon nutritional status and this expression was also perturbed in type I diabetes. In line with this, we showed that insulin elevated the expression of SREBP-1c in primary cultured Schwann cells by activating the SREBP-1c promoter. Taken together, these findings reveal that SREBP-1c expression in Schwann cells responds to metabolic stimuli including insulin and that this response is affected in type I diabetes mellitus. This suggests that disturbed SREBP-1c regulated lipid metabolism may contribute to the pathophysiology of DPN. As a second approach, we performed a comprehensive analysis of the molecular changes associated with DPN in the Akital~1~+ mouse which is a model of spontaneous early-onset type I diabetes mellitus. This mouse expresses a mutated non-functional isoform of insulin, leading to hypoinsulinemia and hyperglycaemia. To determine the onset of DPN, weight, blood glucose and motor nerve conduction velocity (MNCV) were measured in Akital+/+ mice during the first three months of life. A decrease in MNCV was evident akeady one week after the onset of hyperglycemia. To explore the molecular changes associated with the development of DPN in these mice, we performed gene expression profiling using sciatic nerve endoneurium and dorsal root ganglia (DRG) isolated from early diabetic male Akita+/+ mice and sex-matched littermate controls. No major transcriptional changes were detected either in the DRG or in the sciatic nerve endoneurium. This experiment indicates that the phenotypic changes observed during the development of DPN are not correlated with major transcriptional alterations, but mainly with alterations at the protein level. Résumé Lors ce travail, nous nous sommes intéressés aux changements moléculaires aboutissant aux neuropathies périphériques dues au diabète (NPD). Les NPD sont la complication la plus commune du diabète de type I et de type II. Cette pathologie est une cause majeure d'amputations. Même si les changements pathologiques et morphologiques associés aux NPD sont relativement bien décrits, les mécanismes moléculaires provoquant cette pathologie sont mal connus. Deux approches ont principalement été utilisées pour étudier le développement des NPD dans des modèles murins du diabète de type I. Nous avons d'abord étudié l'impact du métabolisme des lipides sur le développement des NPD en nous concentrant sur Sterol Response Element Binding Protein (SREBP)-1 c qui est un régulateur clé des lipides de stockage. Nous avons montré que SREBP-1 c est exprimé dans les nerfs périphériques et que son profil d'expression suit celui de gènes impliqués dans le métabolisme des lipides de stockage. De plus, l'expression de SREBP-1c dans l'endoneurium des nerfs périphériques est dépendante du statut nutritionnel et est dérégulée lors de diabète de type I. Nous avons également pu montrer que l'insuline augmente l'expression de SREBP-1c dans des cultures primaires de cellules de Schwann en activant le promoteur de SREBP-1c. Ses résultats démontrent que l'expression de SREBP-1c dans les cellules de Schwann est contrôlée par des stimuli métaboliques comme l'insuline et que cette réponse est affectée dans le cas d'un diabète de type I. Ces données suggèrent que la dérégulation de l'expression de SREBP-1c lors du diabète pourrait affecter le métabolisme des lipides et ainsi contribuer à la pathophysiologie des NPD. Comme seconde approche, nous avons réalisé une analyse globale des changements moléculaires associés au développement des NPD chez les souris Akita+/+, un modèle de diabète de type I. Cette souris exprime une forme mutée et non fonctionnelle de l'insuline provoquant une hypoinsulinémie et une hyperglycémie. Afin de déterminer le début du développement de la NPD, le poids, le niveau de glucose sanguin et la vitesse de conduction nerveuse (VCN) ont été mesurés durant les 3 premiers mois de vie. Une diminution de la VCN a été détectée une semaine seulement après le développement de l'hyperglycémie. Pour explorer les changements moléculaires associés avec le développement des NPD, nous avons réalisé un profil d'expression de l'endoneurium du nerf sciatique et des ganglions spinaux isolés à partir de souris Akital+/+ et de souris contrôles Akita+/+. Aucune altération transcriptionnelle majeure n'a été détectée dans nos échantillons. Cette expérience suggère que les changements phénotypiques observés durant le développement des NPD ne sont pas corrélés avec des changements importants au niveau transcriptionnel, mais plutôt avec des altérations au niveau protéique. Résumé : Lors ce travail, nous nous sommes intéressés aux changements moléculaires aboutissant aux neuropathies périphériques dues au diabète (NPD). Les NPD sont la complication la plus commune du diabète de type I et de type II. Cette pathologie est une cause majeure d'amputations. Même si les changements pathologiques et morphologiques associés aux NPD sont relativement bien décrits, les mécanismes moléculaires provoquant cette pathologie sont mal connus. Deux approches ont principalement été utilisées pour étudier le développement des NPD dans des modèles murins du diabète de type I. Nous avons d'abord étudié l'impact du métabolisme des lipides sur le développement des NPD en nous concentrant sur Sterol Response Element Binding Protein (SREBP)-1c qui est un régulateur clé des lipides de stockage. Nous avons montré que SREBP-1 c est exprimé dans les nerfs périphériques et que son profil d'expression suit celui de gènes impliqués dans le métabolisme des lipides de stockage. De plus, l'expression de SREBP-1c dans l'endoneurium des nerfs périphériques est dépendante du statut nutritionnel et est dérégulée lors de diabète de type I. Nous avons également pu montrer que l'insuline augmente l'expression de SREBP-1c dans des cultures primaires de cellules de Schwann en activant le promoteur de SREBP-1c. Ses résultats démontrent que l'expression de SREBP-1c dans les cellules de Schwann est contrôlée par des stimuli métaboliques comme l'insuline et que cette réponse est affectée dans le cas d'un diabète de type I. Ces données suggèrent que la dérégulation de l'expression de SREBP-1c lors du diabète pourrait affecter le métabolisme des lipides et ainsi contribuer à la pathophysiologie des NPD. Comme seconde approche, nous avons réalisé une analyse globale des changements moléculaires associés au développement des NPD chez les souris Akita~~Z~+, un modèle de diabète de type I. Cette souris exprime une forme mutée et non fonctionnelle de l'insuline provoquant une hypoinsulinémie et une hyperglycémie. Afin de déterminer le début du développement de la NPD, le poids, le niveau de glucose sanguin et la vitesse de conduction nerveuse (VCN) ont été mesurés durant les 3 premiers mois de vie. Une diminution de la VCN a été détectée une semaine seulement après le développement de l'hyperglycémie. Pour explorer les changements moléculaires associés avec le développement des NPD, nous avons réalisé un profil d'expression de l'endoneurium du nerf sciatique et des ganglions spinaux isolés à partir de souris Akital+/+ et de souris contrôles Akita+/+. Aucune altération transcriptionnelle majeure n'a été détectée dans nos échantillons. Cette expérience suggère que les changements phénotypiques observés durant le développement des NPD ne sont pas corrélés avec des changements importants au niveau transcriptionnel, mais plutôt avec des altérations au niveau protéique.

Are myotonic dystrophy and peripheral neuropathy associated? : morphological, morphometric and electrophysiological analysis in DM1 transgenic mice

Abstract: Myotonic dystrophy (DM1), also known as Steinert disease, is an inherited autosomal dominant disease. It is characterized by myotonia, muscular weakness and atrophy, but DM1 may have manifestations in other organs such as eyes, heart, gonads, gastrointestinal and respiratory tracts, as well as brain. In 1992, it was demonstrated that this complex disease results from the expansion of CTG repeats in the 3' untranslated region of the DM protein kinase (DMPK) gene on chromosome 19. The size of the inherited expansion is critically linked to the severity of the disease and the age of onset. Although several electrophysiological and histological studies have been carried out to verify the possible involvement of peripheral nerve abnormality with DM1, the results have not been univocal. Therefore, at present the possible association between peripheral neuropatliy and DM1 remains debated. Recently, transgenic mice have been generated, that carry the human genomic DM1 region with 300 CTG repeats, and display the human DMl phenotype. The generation of these DM1 transgenic mice provides a useful tool to investigate the type and incidence of structural abnormalities in the peripheral nervous system associated with DM1 disease. By using the DM1 transgenic mice, we investigated the presence/absence of the three major peripheral neuropathies: axonal degeneration, axonal demyelination and neuronopathy. The morphological and morphometric analysis of sciatic, sural and phrenic nerves demonstrated the absence of axonal degeneration or demyelination. The morphometric analysis also ruled out any loss in the numbers of sensory or motor neurons in lumbar dorsal root ganglia and lumbar spinal cord enlargement respectively. Moreover, the éxamination of serial hind limb muscle sections from DMl mice showed a normal intramuscular axonal arborization as well as the absence of changes in the number and structure of endplates. Finally, the electrophysiological tests performed in DM1 transgenic mice showed that the compound muscle axon potentials (CMAPs) elicited in the hind limb digits in response to a stimulation of the sciatic nerve with anear-nerve electrode were similar to thosé obtained in wild type mice. On the basis of all our results, we hypothesized that 300 CTG repeats are not sufficient to induce disorder in the peripheral nervous system of this DM1 transgenic mouse model. Résumé La dystrophie myotonique (DM1), connue aussi sous le nom de maladie de Steinert, est une maladie héréditaire autosornale dominante. Elle est caractérisée par une myotonie, une faiblesse et une atrophie musculaires, mais peut aussi se manifester dans d'autres organes tels que les yeux, les voies digestive et respiratoire, ou le cerveau. En 1992, il a été montré que cette maladie complexe résultait de l'expansion d'une répétition de CTG dans une partie non traduite en 3' du gène codant pour la protéine kinase DM (DMPK), sur le chromosome 19. La taille de l'expansion héritée est étroitement liée à la sévérité et l'âge d'apparition de DM1. Bien que plusieurs études électrophysiologiques et histologiques aient été menées, pour juger d'une implication possible d'anomalies au niveau du système nerveux périphérique dans la DM1, les résultats n'ont jusqu'ici pas été univoques. Aujourd'hui, la question d'une neuropathie associée avec la DM1 reste donc controversée. Des souris transgéniques ont été élaborées, qui portent la séquence DM1 du génome humain avec 300 répétitions CTG et expriment le phénotype des patients DM1: Ces souris transgéniques DMl procurent un outil précieux pour l'étude du type et de l'incidence d'éventuelles anomalies du système nerveux périphérique dans la DM1. En utilisant ces souris transgéniques DM1, nous avons étudié la présence ou l'absence des trois principaux types de neuropathies périphériques: la dégénération axonale, la démyélinisation axonale et la neuronopathie. Les études morphologiques et morphométrique des nerfs sciatiques, suraux et phréniques ont montré l'absence de dégénération axonale ou de démyélinisation. L'analyse du nombre de cellules neuronales n'a pas dévoilé de diminution des nombres de neurones sensitifs dans les ganglions des racines dorsales lombaires ou de neurones moteurs dans la moëlle épinière lombaire des souris transgéniques DMl. De plus, l'examen de coupes sériées de muscle des membres postérieurs de souris DM1 a montré une arborisation axonale intramusculaire normale, de même que l'absence d'irrégularité dans le nombre ou la structure des plaques motrices. Enfin, les tests électrophysiologiques effectués sur les souris DMl ont montré que les potentiels d'action de la composante musculaire (CMAPs) évoqués dans les doigts des membres postérieurs, en réponse à une stimulation du nerf sciatique à l'aide d'une électrode paranerveuse, étaient identiques à ceux observées chez les souris sauvages. Sur la base de l'ensemble de ces résultats, nous avons émis l'hypothèse que 300 répétitions CTG ne sont pas suffisantes pour induire d'altérations dans le système nerveux périphérique du modèle de souris transgéniques DM 1.

Clinical spectrum of tuberculous optic neuropathy.

PURPOSE: Tuberculous optic neuropathy may follow infection with Mycobacterium tuberculosis or administration of the bacille Calmette-Guerin. However, this condition is not well described in the ophthalmic literature. METHODS: Ophthalmologists, identified through professional electronic networks or previous publications, collected standardized clinical data relating to 62 eyes of 49 patients who they had managed with tuberculous optic neuropathy. RESULTS: Tuberculous optic neuropathy was most commonly manifested as papillitis (51.6 %), neuroretinitis (14.5 %), and optic nerve tubercle (11.3 %). Uveitis was an additional ocular morbidity in 88.7 % of eyes. In 36.7 % of patients, extraocular tuberculosis was present. The majority of patients (69.4 %) had resided in and/or traveled to an endemic area. Although initial visual acuity was 20/50 or worse in 62.9 % of 62 eyes, 76.7 % of 60 eyes followed for a median of 12 months achieved visual acuities of 20/40 or better. Visual field defects were reported for 46.8 % of eyes, but these defects recovered in 63.2 % of 19 eyes with follow-up. CONCLUSION: Visual recovery from tuberculous optic neuropathy is common, if the diagnosis is recognized and appropriate treatment is instituted. A tuberculous etiology should be considered when evaluating optic neuropathy in persons from endemic areas.

Diagnostic pitfalls: posterior ischemic optic neuropathy mimicking optic neuritis.

In young people, the most frequent cause of isolated monocular visual loss due to an optic neuropathy is optic neuritis. We present the case of a 27 year old woman who presented monocular visual loss, excruciating orbital pain and unusual temporal headache. The initial diagnosis of optic neuritis revealed later to be a posterior ischemic optic neuropathy (PION). In this case, PION was the first unique presentation of a non-traumatic carotid dissection, and it was followed 24h later by an ischemic stroke. Sudden monocular visual loss associated with a new-onset headache are clinical symptoms that should immediately prompt to a carotid dissection.

Outcomes of optic nerve sheath decompression for nonarteritic ischemic optic neuropathy.

Efficacy of optic nerve sheath decompression (ONSD) in treating non-arteritic ischemic optic neuropathy (NAION) is not clear. We retrospectively analyzed the records of 91 patients with NAION, who were examined during a two-year period, and compared the final Snellen visual acuities of eyes treated with ONSD with those of eyes that did not have surgery. Seven of 18 eyes with ONSD (39%) demonstrated increased visual acuity of two or more lines; whereas 23 of 71 eyes without surgery (32%) had increased acuity. The ONSD group and no surgery group were further subdivided into eyes with progressive visual loss and nonprogressive visual loss. No statistically significant differences in visual outcome between groups were found. We did not find the high frequency of visual improvement that has been reported in some studies of ONSD for NAION.

Peripheral Nerve Neuropathy is Associated with a Glial Reaction in the Gracile Nucleus Associated with a regulation of the GABA transporter GAT-1

Allodynia (pain in response to normally non painful stimulation) and paresthesia (erroneous sensory experience) are two debilitating symptoms of neuropathic pain. These stem, at least partly, from profound changes in the non-nociceptive sensory pathway that comprises large myelinated neuronal afferents terminating in the gracile and cuneate nuclei. Further than neuronal changes, well admitted evidence indicates that glial cells (especially in the spinal cord) are key actors in neuropathic pain, in particular the possible alteration in astrocytic capacity to reuptake neurotransmitters (glutamate and GABA). Yet, the possibility of such a changed astrocytic scavenging capacity remains unexplored in the dorsal column pathway. The present study was therefore undertaken to assess whether peripheral nerve injury (spared nerve injury model, SNI) could trigger a glial reaction, and especially changes in glutamate and GABA transporters, in the gracile nucleus. SNI surgery was performed on male Sprague-Dawley rats. Seven days after surgery, rats were used for immunofluorescence (fixation and brain slicing), western-blot (fresh brain freezing and protein extraction) or GABA reuptake on synaptosomes. We found that SNI results in a profound glial reaction in the ipsilateral gracile nucleus. This reaction was characterized by an enhanced immunolabelling for microglial marker Iba1 as well as astrocytic protein GFAP (further confirmed by western-blot, p <0.05, n = 7). These changes were not observed in sham animals. Immunofluorescence and western-blot analysis shows that the GABA transporter GAT-1 is upregulated in the ipsilateral gracile nucleus (p <0.001; n = 7), with no detectable change in GAT-3 or glutamate transporters EAAT-1 and EAAT-2. Double immunoflurescence shows that GAT-1 and GFAP colocalize within the same cells. Furthermore, the upregulation of GFAP and GAT-1 were shown to occur all along the rostrocaudal axis of the gracile nucleus. Finally, synaptosomes from ipsilateral gracile nucleus show an increased capacity to reuptake GABA. Together, the data presented herein show that glial cells in the gracile nucleus react to neuropathic lesion, in particular through an upregulation of the GABA transporter GAT-1. Hence, this study points to role of an increased GABA transport in the dorsal column nuclei in neuropathic pain, calling attention to GAT-1 as a putative future pharmacological target to treat allodynia and paresthesia.

Diabetic neuropathy is a more important determinant of baroreflex sensitivity than carotid elasticity in type 2 diabetes.

The object of this study was to evaluate the contribution of carotid distensibilty on baroreflex sensitivity in patients with type 2 diabetes mellitus with at least 2 additional cardiovascular risk factors. Carotid distensibility was measured bilaterally at the common carotid artery in 79 consecutive diabetic patients and 60 matched subjects without diabetes. Spontaneous baroreflex sensitivity assessment was obtained using time and frequency methods. Baroreflex sensitivity was lower in diabetic subjects as compared with nondiabetic control subjects (5.25+/-2.80 ms/mm Hg versus 7.55+/-3.79 ms/mm Hg; P<0.01, respectively). Contrary to nondiabetic subjects, diabetic subjects showed no significant correlation between carotid distensibility and baroreflex sensitivity (r2=0.08, P=0.04 and r2=0.04, P=0.13, respectively). In diabetic subjects, baroreflex sensitivity was significantly lower in subjects with peripheral neuropathy than in those with preserved vibration sensation (4.1+/-0.5 versus 6.1+/-0.4 ms/mm Hg, respectively; P=0.005). Age in nondiabetic subjects, diabetes duration, systolic blood pressure, peripheral or sensitive neuropathy, and carotid distensibility were introduced in a stepwise multivariate analysis to identify the determinants of baroreflex sensitivity. In diabetic patients, neuropathy is a more sensitive determinant of baroreflex sensitivity than the reduced carotid distensibility (stepwise analysis; F ratio=5.1, P=0.028 versus F ratio=1.9, P=0.16, respectively). In diabetic subjects with 2 additional cardiovascular risk factors, spontaneous baroreflex sensitivity is not related to carotid distensibility. Diabetic subjects represent a particular population within the spectrum of cardiovascular risk situations because of the marked neuropathy associated with their metabolic disorder. Therefore, neuropathy is a more significant determinant of baroreflex sensitivity than carotid artery elasticity in patients with type 2 diabetes.

Global transcriptional programs in peripheral nerve endoneurium and DRG are resistant to the onset of type 1 diabetic neuropathy in Ins2 mice.

While the morphological and electrophysiological changes underlying diabetic peripheral neuropathy (DPN) are relatively well described, the involved molecular mechanisms remain poorly understood. In this study, we investigated whether phenotypic changes associated with early DPN are correlated with transcriptional alterations in the neuronal (dorsal root ganglia [DRG]) or the glial (endoneurium) compartments of the peripheral nerve. We used Ins2(Akita/+) mice to study transcriptional changes underlying the onset of DPN in type 1 diabetes mellitus (DM). Weight, blood glucose and motor nerve conduction velocity (MNCV) were measured in Ins2(Akita/+) and control mice during the first three months of life in order to determine the onset of DPN. Based on this phenotypic characterization, we performed gene expression profiling using sciatic nerve endoneurium and DRG isolated from pre-symptomatic and early symptomatic Ins2(Akita/+) mice and sex-matched littermate controls. Our phenotypic analysis of Ins2(Akita/+) mice revealed that DPN, as measured by reduced MNCV, is detectable in affected animals already one week after the onset of hyperglycemia. Surprisingly, the onset of DPN was not associated with any major persistent changes in gene expression profiles in either sciatic nerve endoneurium or DRG. Our data thus demonstrated that the transcriptional programs in both endoneurial and neuronal compartments of the peripheral nerve are relatively resistant to the onset of hyperglycemia and hypoinsulinemia suggesting that either minor transcriptional alterations or changes on the proteomic level are responsible for the functional deficits associated with the onset of DPN in type 1 DM.

Pupil responses derived from outer and inner retinal photoreception are normal in patients with hereditary optic neuropathy.

We compared the pupil responses originating from outer versus inner retinal photoreception between patients with isolated hereditary optic neuropathy (HON, n = 8) and healthy controls (n = 8). Three different testing protocols were used. For the first two protocols, a response function of the maximal pupil contraction versus stimulus light intensity was generated and the intensity at which half of the maximal pupil contraction, the half-max intensity, was determined. For the third protocol, the pupil size after light offset, the re-dilation rate and re-dilation amplitude were calculated to assess the post-light stimulus response. Patients with HON had bilateral, symmetric optic atrophy and significant reduction of visual acuity and visual field compared to controls. There were no significant mean differences in the response curve and pupil response parameters that reflect mainly rod, cone or melanopsin activity between patients and controls. In patients, there was a significant correlation between the half-max intensity of the red light sequence and visual field loss. In conclusion, pupil responses derived from outer or inner retinal photoreception in HON patients having mild-to moderate visual dysfunction are not quantitatively different from age-matched controls. However, an association between the degree of visual field loss and the half-max intensity of the cone response suggests that more advanced stages of disease may lead to impaired pupil light reflexes.

KIAA1985, a Protein Mutant in Charcot-Marie-Tooth Neuropathy, Links Peripheral Nerve Myelination to Endosomal Recycling Pathways

Charcot-Marie-Tooth neuropathy (CMT) represents a heterogenous group of inherited disorders of the peripheral nervous system. One form of autosomal recessive demyelinating CMT (CMT4C, 5q32) is caused by mutations in the gene encoding KIAA1985, a protein of so far unknown function. Here we show that KIAA1985 is exclusively expressed in Schwann cells. KIAA1985 is tethered to cellular membranes through an N-terminal myristic acid anchor and localizes to the perinuclear recycling compartment. A search for proteins that interact with KIAA1985 identified the small GTPase Rab11, a key regulator of recycling endosome functions. CMT4C-related missense mutations disrupt the KIAA1985/Rab11 interaction. Protein binding studies indicate that KIAA1985 functions as a Rab11 effector, as it interacts only with active forms of Rab11 (WT and Q70L) and does not interact with the GDP locked mutant (S25N). Consistent with a function of Rab11 in Schwann cell myelination, myelin formation was strongly impaired when dorsal root ganglion neurons were co-cultured with Schwann cells infected with Rab11 S25N. Our data indicate that the KIAA1985/Rab11 interaction is relevant for peripheral nerve pathophysiology and place endosomal recycling on the list of cellular mechanisms involved in Schwann cell myelination.