Exclusion of the ninjurin gene as a candidate for hereditary sensory neuropathies type I and type II

Ninjurin is a protein that is up-regulated in Schwann cells and neurons after peripheral nerve injury. Its role in promoting nerve regeneration and its expression in sensory neurons of dorsal root ganglia, as well as the chromosomal localization of the ninjurin gene, makes this gene a candidate for hereditary sensory neuropathies (HSN). In the present report, the human ninjurin gene was analyzed in 17 unrelated patients with HSN type I, two patients with HSN type II, and 10 normal controls, by single strand conformation polymorphism and by direct sequencing. All three exons and splice junctions of the gene were investigated and no mutations were found in our sample of patients. Our results rule out a mutation in the translated region of the ninjurin gene as a cause of HSN type I and type II.     

Analysis of LMNB1 Duplications in Autosomal Dominant Leukodystrophy Provides Insights into Duplication Mechanisms and Allele‐Specific Expression

Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication‐based mechanisms such fork stalling and template switching or microhomology‐mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients’ fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele‐specific LMNB1 expression levels.     

Variations in the NMDA receptor subunit 2B gene (GRIN2B) and schizophrenia: a case-control study.

A well established model for the pathophysiology of schizophrenia postulates a role for the NMDA-mediated glutamate transmission. The human gene coding for the 2B subunit of the NMDA receptor (GRIN2B) is considered a candidate based on its selective expression in brain. To evaluate the hypothesis that GRIN2B acts as a major gene in determining susceptibility to schizophrenia, a case-control association study was performed. Five single nucleotide polymorphisms (SNPs) were genotyped in 188 Italian patients and 156 control subjects. The association study showed a marginally significant excess of homozygosity for the polymorphism located in the 3'UTR region (P = 0.04). No other difference in genotype and allele frequencies was found in schizophrenics as compared to the control series. The case-control study was also carried out on estimated haplotypes, confirming a trend for association (P = 0.04). These results suggest that GRIN2B variations might be linked with susceptibility to schizophrenia. Replication studies on larger samples are warranted to further test this hypothesis.     

Differences in risk factors for breast cancer molecular subtypes in a population-based study.

Analysis of gene expression data suggests that breast cancers are divisible into molecular subtypes which have distinct clinical features. This study evaluates whether pathologic features and etiologic associations differ among molecular subtypes. We evaluated 804 women with invasive breast cancers and 2,502 controls participating in a Polish Breast Cancer Study. Immunohistochemical stains for estrogen receptor alpha, progesterone receptor, human epidermal growth factor receptors (HER2 and HER1), and cytokeratin 5 were used to classify cases into five molecular subtypes: luminal A, luminal B, HER2-expresing, basal-like, and unclassified. Relative risks were estimated using adjusted odds ratios and 95% confidence intervals. We observed that compared with the predominant luminal A tumors (69%), other subtypes were associated with unfavorable clinical features at diagnosis, especially HER2-expressing (8%) and basal-like (12%) tumors. Increasing body mass index significantly reduced the risk of luminal A tumors among premenopausal women (odds ratios, 0.71; 95% confidence intervals, 0.57-0.88 per five-unit increase), whereas it did not reduce risk for basal-like tumors (1.18; 0.86-1.64; P(heterogeneity) = 0.003). On the other hand, reduced risk associated with increasing age at menarche was stronger for basal-like (0.78; 0.68-0.89 per 2-year increase) than luminal A tumors (0.90; 0.95-1.08; P(heterogeneity) = 0.0009). Although family history increased risk for all subtypes (except for unclassified tumors), the magnitude of the relative risk was highest for basal-like tumors. Results from this study have shown that breast cancer risk factors may vary by molecular subtypes identified in expression studies, suggesting etiologic, in addition to clinical, heterogeneity of breast cancer.     

Nutritional status, brain development and scholastic achievement of Chilean high-school graduates from high and low intellectual quotient and socio-economic status

The objective of the present study was to investigate the inter-relationships between nutritional status (past and current nutrition), brain development, and scholastic achievement (SA) of Chilean high-school graduates from high and low intellectual quotient (IQ) and socio-economic status (SES) (mean age 18.0 (SD 0.9) years). Results showed that independently of SES, high-school graduates with similar IQ have similar nutritional, brain development and SA variables. Multiple regression analysis between child IQ (dependent variable) and age, sex, SES, brain volume (BV), undernutrition during the first year of life, paternal and maternal IQ (independent variables) revealed that maternal IQ (P<0.0001), BV (P<00387) and severe undernutrition during the first year of life (P<0.0486), were the independent variables with the greatest explanatory power for child IQ variance (r2 0.707), without interaction with age, sex or SES. Child IQ (P<0.0001) was the only independent variable that explained both SA variance (r2 0.848) and academic aptitude test variance (r2 0.876) without interaction with age, sex or SES. These results confirm the hypotheses formulated for this study that: (1) independently of SES, high-school graduates with similar IQ have similar variables of nutritional status, brain development and SA; (2) past nutritional status, brain development, child IQ and SA are strongly and significantly inter-related. These findings are relevant in explaining the complex interactions between variables that affect IQ and SA and can be useful for nutritional and educational planning.     

Multifocal bilateral renal cell carcinoma and retinal angiomas in a patient with de novo von Hippel-Lindau disease: identification of a new germline mutation

Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder characterized by multifocal and bilateral renal cell carcinoma and cysts, retinal angiomas, hemangioblastoma of the central nervous system, pheochromocytoma, epididymis cystoadenoma, pancreatic cysts and/or islet cell tumors. However, phenotypic manifestations and clinical outcome are wide ranging including inter and intra-familial patterns. The VHL gene has been localized on chromosome 3 p 25-26 and more than 250 germline mutations have been described. The sensitivity of analytic techniques of VHL gene is close to 100%. It is well known that about 25% of VHL patients present de novo mutations, and first cases function as possible founders of new VHL kindreds. Herein, we report the clinical case of a 45-year-old Caucasian female patient affected by bilateral polycystic kidney disease with two renal carcinomas in both kidneys without lynphoadenopathies. She underwent ophthalmologic surgery at 19 years old because of retinal detachment due to bilateral retinal angiomatosis. Direct gene sequencing showed a deletion-insertion in exon 3, starting from nucleotide 499 of the coding sequence (c.499-504 delinstT) in a heterozygous status; it causes a frame-shift and creates a premature stop at codon 170. The genetic study of the unaffected parents and of the unaffected brother confirmed the diagnosis of de novo VHL disease with the dentification of a new germline mutation, never reported in the literature. The patient showed normal kidney function and she did not show other organ lesions or clinical manifestations of VHL disease. She was successfully submitted to renal parenchymal sparing-surgery. In conclusion, it is important to test for germline mutations in VHL patients with the involvement of one organ or a pair of organs. Once the mutation is found in the proband, all family members can be easily tested for the documented mutation. The early identification of VHL patients is very important for clinical and genetic reasons.     

A novel mutation of myelin protein zero associated with an axonal form of Charcot-Marie-Tooth disease

OBJECTIVE: To report a new mutation in the MPZ gene which encodes myelin protein zero (P0), associated with an axonal form of Charcot-Marie-Tooth disease (CMT). METHODS: Three patients from an Italian family with a mild, late onset axonal peripheral neuropathy are described clinically and electrophysiologically. To detect point mutation in MPZ gene the whole coding sequence was examined. The structure of the mutated protein was investigated using the three dimensional model of P0. RESULTS: All patients showed a relatively mild CMT phenotype characterised by late onset and heterogeneity of the clinical and electrophysiological features. Molecular analysis demonstrated a novel heterozygous T/A transversion in the exon 3 of MPZ gene that predicts an Asp109Glu amino acid substitution in the extracellular domain of the P0. Asp109 is found at the protein surface, on beta strand E, in the interior of the P0 tetramer. CONCLUSIONS: The identification of Asp109Glu mutation confirms the pivotal role of P0 in axonal neuropathies and stresses the phenotypic heterogeneity associated with MPZ mutations. This study suggests the value of screening for MPZ mutations in CMT family members with minor clinical and electrophysiological signs of peripheral neuropathy.     

A novel mutation of GDAP1 associated with Charcot-Marie-Tooth disease in three Italian families: evidence for a founder effect

BACKGROUND: Mutations in a gene encoding a novel protein of unknown function-the ganglioside-induced differentiation-associated protein 1 gene (GDAP1)-are associated with the autosomal recessive Charcot-Marie-Tooth disease type 4A (CMT4A). OBJECTIVE: To investigate the role of GDAP1 mutations in causing autosomal recessive neuropathies in an Italian population. METHODS AND RESULTS: 76 patients with severe early onset polyneuropathy and possible autosomal recessive inheritance were screened for mutations. A T>G transversion (c.347 T>G) at codon 116 (M116R) was detected in four affected subjects from three apparently unrelated families. All patients had early onset of disease with pronounced foot deformities and impaired walking. Neurophysiological studies showed an extremely variable expression. Sural nerve biopsies revealed signs of both de-remyelination and axonal impairment, the most prominent feature being a severe loss of larger fibres. Haplotype analysis of the GDAP1 locus demonstrated a common disease haplotype. CONCLUSIONS: The association of the mutation with a common haplotype suggested a common ancestor.