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This study reports the characterization of a novel human gene, chromosome 3 open reading frame 6 (C3orf6), mapped to chromosome 3q28, within the critical region of hereditary spastic paraplegia SPG14 locus. Based on computational "spliced" EST alignment and RT-PCR, two C3orf6 transcript variants were identified. The longer C3orf6 transcript contains a 1449-nt ORF, encoding a protein of 482 aa, while the shorter variant contains a 921-nt ORF, encoding for a protein of 306 aa. C3orf6 gene is organised on 12 exons and the shorter transcript comes from an alternative splicing event skipping exon 6. The two mRNA are differentially expressed in brain and in several other human tissues with a predominant level for the shorter transcript. By database analysis, EST assembling and RT-PCR, we identified the transcripts of mouse and rat C3orf6 orthologous genes. The involvement of C3orf6 in the spastic paraplegia was investigated by sequencing all coding exons and flanking sequences in the SPG14 family, excluding the presence of causative mutations.

A genotype-phenotype study based on the primary clinical features of adult myotonic dystrophy (DM) included 116 patients from 62 Italian pedigrees. A significant correlation between clinical severity and the number of repeats at the 3′ untranslated region of the myotonin-protein kinase gene (MT-PK) was found. These results suggest that the CTG amplification is directly related to the myotonic dystrophy phenotype and provide important information on morbidity and prognosis in this disease.

The clinical features to establish the diagnosis of X-linked Emery-Dreifuss muscular dystrophy (EMD) were recently redefined at the European EMD workshop in Baarn 1991. These criteria were used to select families from the literature and two new families for linkage analysis with the DNA markers F9, DX52, DXS15, F8C and DXS115. Recombinations are observed with the DNA markers F9, DXS52 and DXS15. No recombinations were found with F8C and DXS115. Multipoint linkage analysis indicates with a maximum location score of 73.9 that the EMD locus maps very close to F8C.

Congenital hypomyelination neuropathy (CHN) has been related with mutations of the MPZ gene that codes for P0, the major structural protein of the peripheral myelin and of EGR2/Krox20 gene that codes for a transcription factor essential for the normal development of myelinating Schwann cell. More recently, we reported the association between CHN and a Ser72Leu mutation of the peripheral myelin protein 22 (PMP22), a quantitatively minor component of the compact myelin of peripheral nerves, whose functions are still debated. Here we describe a second patient with CHN associated with a novel mutation of PMP22. The patient is the 4-year-old daughter of healthy nonconsanguineous parents and is affected with early delay of motor development. At seven years she could not walk without support; examination disclosed muscle weakness and atrophy, foot drop, pes cavus, scoliosis, areflexia, and impairment of all sensory modalities. MNCV at the median nerve was 3.6 m/s. Nerve biopsy disclosed marked loss of fibers; residual fibers were devoid of myelin or encircled by extremely thin myelin sheaths and were surrounded by basal laminae onion bulbs. Clinical follow up demonstrated no progression of the disease. Molecular analysis disclosed a novel heterozygous T-to-C transition at nucleotide 374 of PMP22, that is predicted to cause a nonconservative substitution of cysteine109 (a phylogenetically conserved residue) with arginine, in the third transmembrane domain. The duplication of PMP22 causes the common demyelinating form of Charcot-Marie-Tooth neuropathy type 1 (CMT1). Our reports indicate that missense mutations of the same protein may cause dysmyelination rather than demyelination, and prompt to investigate the function of PMP22 in myelinogenesis as well as in Schwann cell differentiation.