Deleterious GRM1 Mutations in Schizophrenia

We analysed a phenotypically well-characterised sample of 450 schziophrenia patients and 605 controls for rare non-synonymous single nucleotide polymorphisms (nsSNPs) in the GRM1 gene, their functional effects and family segregation. GRM1 encodes the metabotropic glutamate receptor 1 (mGluR1), whose documented role as a modulator of neuronal signalling and synaptic plasticity makes it a plausible schizophrenia candidate. In a recent study, this gene was shown to harbour a cluster of deleterious nsSNPs within a functionally important domain of the receptor, in patients with schizophrenia and bipolar disorder. Our Sanger sequencing of the GRM1 coding regions detected equal numbers of nsSNPs in cases and controls, however the two groups differed in terms of the potential effects of the variants on receptor function: 6/6 case-specific and only 1/6 control-specific nsSNPs were predicted to be deleterious. Our in-vitro experimental follow-up of the case-specific mutants showed that 4/6 led to significantly reduced inositol phosphate production, indicating impaired function of the major mGluR1signalling pathway; 1/6 had reduced cell membrane expression; inconclusive results were obtained in 1/6. Family segregation analysis indicated that these deleterious nsSNPs were inherited. Interestingly, four of the families were affected by multiple neuropsychiatric conditions, not limited to schizophrenia, and the mutations were detected in relatives with schizophrenia, depression and anxiety, drug and alcohol dependence, and epilepsy. Our findings suggest a possible mGluR1 contribution to diverse psychiatric conditions, supporting the modulatory role of the receptor in such conditions as proposed previously on the basis of in vitro experiments and animal studies

The stretcher spontaneous neurodegenerative mutation models Charcot-Marie-Tooth disease type 4D.

Mice affected by a spontaneous mutation which arose within our colony exhibited a neuromuscular phenotype involving tremor and characteristic stretching of the rear limbs. The mutant, named stretcher, was used to breed a backcross cohort for genetic mapping studies. The gene responsible for the mutant phenotype was mapped to a small region on mouse chromosome 15, with a LOD score above 20. Candidate genes within the region included the Ndrg1 gene. Examination of this gene in the mutant mouse strain revealed that exons 10 to 14 had been deleted. Mutations in the human orthologue are known to result in Charcot-Marie-Tooth disease type 4D (CMT4D) a severe early-onset disorder involving Schwann cell dysfunction and extensive demyelination. The stretcher mutant mouse is more severely affected than mice in which the Ndrg1 gene had been knocked out by homologous recombination. Our results demonstrate that the Ndrg1 (str) mutation provides a new model for CMT4D, and demonstrate that exons 10 to 14 of Ndrg1 encode amino acids crucial to the appropriate function of Ndrg1 in the central nervous system

Hereditary auditory, vestibular, motor, and sensory neuropathy in a Slovenian Roma (Gypsy) kindred.

Members of a Roma (Gypsy) family with hereditary motor and sensory peripheral neuropathy (HMSN) and concomitant auditory and vestibular cranial neuropathies were identified in Kocevje, Slovenia. The illness begins in childhood with a severe and progressive motor disability and the deafness is delayed until the second decade. There are no symptoms of vestibular dysfunction. The family structure is consistent with an autosomal recessive pattern of inheritance and the genetic locus for the disorder is linked to the same region of chromosome 8q24 as other Roma families with HMSN and deafness from Lom, Bulgaria (HMSN-Lom). The present study shows that the deafness is caused by a neuropathy of the auditory nerve with preserved measures of cochlear outer hair cell function (otoacoustic emissions and cochlear microphonics) but absent neural components of auditory brainstem potentials. The hearing loss affects speech comprehension out of proportion to the pure tone loss. Vestibular testing showed absence of caloric responses. Physiological and neuropathological studies of peripheral nerves were compatible with the nerve disorder contemporaneously affecting Schwann cells and axons resulting in both slowed nerve conduction and axonal loss. Genetic linkage studies suggest a refinement of the 8q24 critical region containing the HMSN-Lom locus that affects peripheral motor and sensory nerves as well as the cranial auditory and vestibular nerves

A novel Gypsy founder mutation, p.Arg1109X in the CMT4C gene, causes variable peripheral neuropathy phenotypes

Background: Linkage, haplotype and sequencing analysis in a large Spanish Gypsy kindred with multiple members affected by autosomal recessive peripheral neuropathy led to the identification of a novel mutation, p.Arg1109X, in the CMT4C gene. The screening of further unrelated patients, and of a panel of ethnically matched controls, showed that p.Arg1109X is an ancestral mutation which occurs in Gypsy populations across Europe and is the most common cause of autosomal recessive Charcot–Marie–Tooth disease in Spanish Gypsies. Objective: To report the identification of a novel Gypsy founder mutation causing autosomal recessive CMT4C disease in a sample of homozygous affected individuals. Results: The mutation was associated with a surprisingly broad spectrum of neuropathy phenotypes, with variation in the age at onset, rate of progression, severity of muscle and sensory involvement, the presence of scoliosis, and cranial nerve involvement. Conclusions: Ascertainment and further studies of CMT4C patients in this population will provide a unique opportunity for characterising the full range of clinical manifestations of the disease in a genetically homogeneous sample