Three novel mutations and two variants in the gene for Cu/Zn superoxide dismutase in familial amyotrophic lateral sclerosis.

Autosomal dominant inheritance is exhibited by about 10% of cases of amyotrophic lateral sclerosis (ALS), a paralytic disorder characterized by the death of motor neurons in the brain and spinal cord. A subgroup of these familial cases are linked to mutations in the gene which codes for Cu/Zn superoxide dismutase (SOD1). We report three additional mutations occurring in the SOD1 gene in ALS patients and two single base pair variant changes. The single base pair change in an ALS family causes a glycine 93 to valine substitution, which is the fifth distinct amino acid change reported for the glycine 93 residue. One missense mutation in exon 5 would substitute neutral valine for the negatively-charged aspartate 124 (aspartate 124 to valine). An individual with an apparently sporadic case of ALS carries a three base pair deletion in exon 5 of the SOD1 gene. These three mutations bring to 38 the total number of distinct SOD1 mutations associated with familial ALS.

The gene for hereditary sensory neuropathy type I (HSN-I) maps to chromosome 9q22.1-q22.3.

Hereditary sensory neuropathy type I (HSN-I, also known as hereditary sensory and autonomic neuropathy type I (HSAN-I), or hereditary sensory radicular neuropathy) is an autosomal dominant disorder that is the most common of a group of degenerative disorders of sensory neurons. HSN-I was initially recognized as a disease that produced mutilating ulceration leading to amputation of digits (Fig. 1). It was given names such as familial ulcers with mutilating lesions of the extremities and perforating ulcers with osseous atrophy. The disease involves a progressive degeneration of dorsal root ganglion and motor neurons, leading to distal sensory loss and later distal muscle wasting and weakness and variable neural deafness. Sensory deficits include loss of all modalities, particularly loss of sensation to pain and temperature. Skin injuries may lead to chronic skin ulcers, osteomyelitis, and extrusion of bone fragments, especially the metatarsals. Onset of symptoms is in the second or later decades. We undertook a genome screen using linkage analysis in four Australian HSN-I kindreds. We now show that the HSN1 gene maps to an 8-centiMorgan (cM) region flanked by D9S318 and D9S176 on chromosome 9q22.1-q22.3. Multipoint linkage analysis suggests a most likely location at D9S287, within a 4.9-cM confidence interval.

A frame shift mutation in the PMP22 gene in hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) has been a associated with a deletion of 1.5 megabases of chromosome 17p. One of four biopsy proven HNPP families that we have studied did not possess this deletion. As the deleted DNA region includes the coding region for a peripheral myelin gene (PMP22), we used single strand conformation analysis to examine this gene for mutations in the non-deleted HNPP family. An abnormal fragment in exon 1 was identified, and sequencing revealed a two base pair deletion in all affected family members. The deletion results in a frame shift, providing strong evidence that this gene has an important role in the pathogenesis of the disease.