Olga Messina-Baas

Novel Mutation and White Matter Involvement in an Indian Child with Pycnodysostosis

Pycnodysostosis (OMIM # 265800) is an inherited lysosomal disorder due to affection of cathepsin K gene, localised to 1q21. Pycnodysostosis can present with both skeletal and extraskeletal features. The index patient presented with cardinal features of short stature, dental and digital anomalies with history of multiple fractures. He, in addition had an unreported finding of white matter hyperintensity suggesting dysmyelination on neuroimaging. Molecular analysis revealed a homozygous insertion of single nucleotide in exon 5 of the CTSK gene that produces the substitution of phenylalanine instead of leucine at position 160 of protein and a premature termination of protein synthesis due to insertion of a stop codon. This mutation (c.480_481insT), (p.L160fsX173) is a novel frameshift mutation. The index case extends the phenotypic spectrum and the list of previously reported mutations in the CTSK gene.

A family with hereditary hyperferritinaemia cataract syndrome: evidence of incomplete penetrance and clinical heterogeneity

Ferritin, the major intracellular iron store protein, consists of 24 subunits of two types, H (heavy) and L (light) encoded in chromosomes 11 and 19, respectively (Worwood, 1982). Ferritin synthesis is regulated by iron intracellular levels; when the supply of iron to the cell is limited, ferritin translation is inhibited, conversely, when cellular iron is abundant ferritin synthesis takes place. The binding of the 5¢ untranslated region (5¢-UTR) of FTL mRNA to trans-acting iron regulatory proteins (IRPs) prevents the binding of the translation initiation complex and thus blocks translation of the ferritin protein (Muckenthaler et al, 1998). Mutations in the 5¢UTR of the FTL gene produce elevated serum ferritin and clinically result in hereditary hyperferritinaemia cataract syndrome (HHCS), an autosomal dominant disease characterized by early onset bilateral cataract. The present study analyzed a family with bilateral cataract and marked hyperferritinaemia. Genomic DNA was isolated from peripheral blood with conventional methods and the FTL gene, including IRE (Iron Regulatory Element) region, was amplified as described elsewhere (Allerson et al, 1999). DNA sequencing analysis was performed in ABI PRISM 310 genetic analyzer (Applied Biosystems, Foster City, CA) according supplier’s conditions. The family with hyperferitinaemia was detected through a oneyear screening programme of patients with early onset cataract (50 non-related patients or families). All assays were performed two times with a normal control included. Clinical characteristics of lens opacities were analyzed through slitlamp. The affected family was referred to the General Hospital of Mexico. The protocol was approved by the Ethics Committee and patients gave informed consent to the study. We analyzed a three-generation Mexican family segregating autosomal

Inherited Congenital Cataract: A Guide to Suspect the Genetic Etiology in the Cataract Genesis

Cataracts are the principal cause of treatable blindness worldwide. Inherited congenital cataract (CC) shows all types of inheritance patterns in a syndromic and nonsyndromic form. There are more than 100 genes associated with cataract with a predominance of autosomal dominant inheritance. A cataract is defined as an opacity of the lens producing a variation of the refractive index of the lens. This variation derives from modifications in the lens structure resulting in light scattering, frequently a consequence of a significant concentration of high-molecular-weight protein aggregates. The aim of this review is to introduce a guide to identify the gene involved in inherited CC. Due to the manifold clinical and genetic heterogeneity, we discarded the cataract phenotype as a cardinal sign; a 4-group classification with the genes implicated in inherited CC is proposed. We consider that this classification will assist in identifying the probable gene involved in inherited CC.

Whole Exome Sequencing Reveals a Mutation in CRYBB2 in a Large Mexican Family with Autosomal Dominant Pulverulent Cataract

Congenital cataract, an important cause of reversible blindness, is due to several causes including Mendelian inheritance. Thirty percent of cataracts are hereditary with participation of the gamma crystallin genes. Clinical and genetic heterogeneity is observed in patients with gene mutations and congenital cataract; about 40 genetic loci have been associated with hereditary cataract. In this study, we identified the underlying genetic cause of an autosomal dominant pulverulent cataract (ADPC) in a large Mexican family. Twenty-one affected patients and 20 healthy members of a family with ADPC were included. Genomic DNA was analyzed by whole exome sequencing in the proband, a normal daughter, and in an affected son, whereas DNA Sanger sequencing was performed in all members of the family. After the bioinformatics analysis, all samples were genotyped using Sanger sequencing to eliminate variants that do not cosegregate with the cataract. We observed a perfect cosegregation of a nonsense mutation c.475C>T (p.Q155*) in exon 6 of the CRYBB2 gene with ADPC. We calculated a logarithm of the odds score of 5.5. This mutation was not detected in healthy members of the family and in 100 normal controls. This is the first Mexican family with ADPC associated with a p.Q155* mutation. Interestingly, this specific mutation in the CRYBB2 gene seems to be exclusively associated with pulverulent/cerulean cataract (with some clinical variability) independent of the populations genetic background.

Familial Blau syndrome without uveitis caused by a novel mutation in the nucleotide-binding oligomerization domain-containing protein 2 gene with good response to infliximab

The proband in this study was a 4‐year‐old Mexican girl with Blau syndrome. She and her affected family members had skin rash and arthritis but no uveitis. Exome sequencing and DNA direct sequencing from blood samples revealed a novel nucleotide‐binding oligomerization domain‐containing protein 2 gene mutation in the affected family members. This study is the first report of a Mexican family with Blau syndrome showing good infliximab treatment response. The novel mutation in the nucleotide‐binding oligomerization domain‐containing protein 2 gene (c.1808A>G) enriches the mutation spectrum in Blau syndrome. This family represents one of the few cases of autosomal Blau syndrome with no uveitis; because of phenotype variability, it is important to recognize Blau syndromes clinical spectrum and recommend genetic consultation.

Discordant retinoblastoma in monozygotic twins due to deletion of 13q14.

Purpose To report discordant retinoblastoma in monozygotic twins, confirmed by GeneScan. Methods One twin presented unilateral retinoblastoma that was treated with enucleation; the other twin had no retinoblastoma. To confirm monozygosity, DNA from leukocytes was analyzed through GeneScan with highly polymorphic markers; to exclude 13q14 deletion, FISH analysis was performed in leukocytes and oral cells of both twins and their parents and in retinal tissue of the affected twin with the cDNA LSI RB1 probe. Results GeneScan analysis confirmed monozygosity. 13q14 deletion was observed in homozygous state in retinal tissue and in heterozygous state in oral cells and leukocytes of the affected twin. The nonaffected twin and parents showed no deletion of 13q14. Conclusions These data show unexpected differences in monozygotic twins that could be explained by postzygotic events in embryonic development.