A novel dominant mutation in CRYAB gene leading to a severe phenotype with childhood onset.

BACKGROUND: αB-crystallin is a promiscuous protein involved in numerous cell functions. Mutations in CRYAB have been found in patients with different pathological phenotypes that are not properly understood. Patients can present different diseases like cataracts, muscle weakness, myopathy, cardiomyopathy, respiratory insufficiency or dysphagia, but also a variable combination of these pathologies has been found. These mutations can show either autosomal dominant or recessive mode of inheritance and variable penetrance and expressivity. This is the first report of congenital cataracts and myopathy described in childhood due to a CRYAB mutation with autosomal dominant mode of inheritance. METHODS: The whole exome sequence was subjected to phenotype-driven analysis and a novel variant in CRYAB was detected: c.514delG, p.(Ala172ProfsTer14). The mutation was located in the C-terminal domain of the protein, which is essential for chaperone activity. The deduced protein was analyzed searching for alterations of the relevant physico-chemical properties described for this domain. A muscle biopsy was also tested for CRYAB with immunohistochemical and histoenzymatic techniques. RESULTS: CRYAB displayed a mild immunoreactivity in the subsarcolemmal compartment with no pathological sarcoplasmic accumulation. It agrees with an alteration of the physico-chemical properties predicted for the C-terminal domain: hydrophobicity, stiffness, and isomerization. CONCLUSIONS: The described mutation leads to elongation of the protein at the carboxi-terminal domain (CTD) with altered properties, which are essential for solubility and activity. It suggests that can be the cause of the severe conditions observed in this patient.

Deleciones intragénicas NRXN1: aportación de tres nuevos casos y revisión del fenotipo / Intragenic deletions of NRXN1: three new case reports and a review of the phenotype

Objetivo. Aportar datos sobre el fenotipo determinado por las microdeleciones de los exones α del gen NRXN1. Casos clínicos. Se estudian tres casos neuropediátricos con microdeleciones intragénicas NRXN1 α. El fenotipo en estos tres casos es inespecífico, con retraso mental leve-moderado, trastornos de comportamiento y escasos rasgos dismórficos o malformaciones. Conclusión. El fenotipo encontrado en las microdeleciones de los exones α del gen NRXN1 es claramente distinguible del fenotipo encontrado en las microdeleciones de los exones β, con macrocefalia, epilepsia y retraso mental (AU)

Aim. To offer data on the phenotype determined by microdeletions of α exons in the NRXN1 gene. Case reports. Three neuropaediatric cases of intragenic microdeletions of NRXN1 α are studied. The phenotype of these three cases is unspecific, with mild-moderate mental retardation, behavioural disorders and slight dysmorphic traits or malformations. Conclusions. The phenotype found in the microdeletions of α exons of the NRXN1 gene is clearly distinguishable from the one found in the microdeletions of β exons, with macrocephaly, epilepsy and mental retardation (AU)

[Intragenic deletions of NRXN1: three new case reports and a review of the phenotype]. / Deleciones intragénicas NRXN1: aportación de tres nuevos casos y revisión del fenotipo.

AIM: To offer data on the phenotype determined by microdeletions of alpha exons in the NRXN1 gene. CASE REPORTS: Three neuropaediatric cases of intragenic microdeletions of NRXN1 alpha are studied. The phenotype of these three cases is unspecific, with mild-moderate mental retardation, behavioural disorders and slight dysmorphic traits or malformations. CONCLUSIONS: The phenotype found in the microdeletions of alpha exons of the NRXN1 gene is clearly distinguishable from the one found in the microdeletions of beta exons, with macrocephaly, epilepsy and mental retardation.

TITLE: Deleciones intragenicas NRXN1: aportacion de tres nuevos casos y revision del fenotipo.Objetivo. Aportar datos sobre el fenotipo determinado por las microdeleciones de los exones alfa del gen NRXN1. Casos clinicos. Se estudian tres casos neuropediatricos con microdeleciones intragenicas NRXN1 alfa. El fenotipo en estos tres casos es inespecifico, con retraso mental leve-moderado, trastornos de comportamiento y escasos rasgos dismorficos o malformaciones. Conclusion. El fenotipo encontrado en las microdeleciones de los exones alfa del gen NRXN1 es claramente distinguible del fenotipo encontrado en las microdeleciones de los exones beta, con macrocefalia, epilepsia y retraso mental.