ClinVar Genomic variation as it relates to human health

Auer-Grumbach et al. (2010) reported a large 5-generation family in which 10 individuals with a neuromuscular disease carried the same heterozygous c.943C-T transition in exon 6 of the TRPV4 gene, resulting in an arg315-to-trp (R315W) substitution. Four patients had hereditary motor and sensory neuropathy type IIC (HMSN2C; 606071), 1 had distal hereditary motor neuropathy, type VIII (HMND8; 600175), and 2 had scapuloperoneal spinal muscular atrophy (SPSMA; 181405). Inheritance was autosomal dominant. The R315W mutation was also identified in an unrelated family in which 6 members had HMSN2C (McEntagart et al., 2005). The mutation was not found in 304 control individuals. The R315W mutation occurred at the outer helices of the ANK4 and ANK5 domains in the N-terminal cytoplasmic domain. In vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had reduced surface expression. In cotransfection studies, both mutant and wildtype proteins were detected in cytoplasmic aggregates. Mutant TRPV4 cells showed an impaired response to stimulus-dependent channel activity. The studies indicated that the mutation interferes with normal channel trafficking and function. Haploinsufficiency was proposed as the most likely underlying mechanism, although a gain of function could not be fully excluded. Chen et al. (2010) identified a heterozygous R315W mutation in a 47-year-old mother and her 26-year-old daughter with HMSN2C and vocal cord paresis; the family had originally been reported by Dyck et al. (1994). Both patients had onset in infancy and developed a relatively severe form of distal muscle weakness and distal sensory loss, as well as short stature. Aharoni et al. (2011) reported a 3-generation family of Ashkenazi/Sephardic Jewish origin with variable expression of HMSN2C due to a heterozygous R315W TRPV4 mutation. Five mutation carriers in 1 family were studied. The proband was a girl who presented at birth with inspiratory stridor, clubfeet, congenital hip dislocation, and knee contractures. She had absent reflexes and bilateral vocal cord paresis requiring tracheostomy. In childhood, she showed delayed motor development, progressive distal amyotrophy and weakness, weakness of the shoulder girdle, scoliosis, and pectus excavatum. Neurophysiologic studies showed an axonal sensorimotor neuropathy. Two of her affected brothers also presented with stridor in infancy and showed a similar phenotype, but without electrophysiologic examination. The mother showed a milder phenotype; she reported being unathletic as a child and having a hoarse voice. In her thirties, she developed slowly progressive fatigue associated with mild distal muscle atrophy in the lower limbs. She had poor reflexes and minimal distal temperature sensitivity. Electrophysiologic studies showed a sensorimotor neuropathy. One mutation carrier in this family was clinically unaffected at age 14 years, although deep tendon reflexes were difficult to elicit. (less)

Auer-Grumbach et al. (2010) reported a large 5-generation family in which 10 individuals with a neuromuscular disease carried the same heterozygous c.943C-T transition in exon 6 of the TRPV4 gene, resulting in an arg315-to-trp (R315W) substitution. Four patients had hereditary motor and sensory neuropathy type IIC (HMSN2C; 606071), 1 had distal hereditary motor neuropathy, type VIII (HMND8; 600175), and 2 had scapuloperoneal spinal muscular atrophy (SPSMA; 181405). Inheritance was autosomal dominant. The R315W mutation was also identified in an unrelated family in which 6 members had HMSN2C (McEntagart et al., 2005). The mutation was not found in 304 control individuals. The R315W mutation occurred at the outer helices of the ANK4 and ANK5 domains in the N-terminal cytoplasmic domain. In vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had reduced surface expression. In cotransfection studies, both mutant and wildtype proteins were detected in cytoplasmic aggregates. Mutant TRPV4 cells showed an impaired response to stimulus-dependent channel activity. The studies indicated that the mutation interferes with normal channel trafficking and function. Haploinsufficiency was proposed as the most likely underlying mechanism, although a gain of function could not be fully excluded. Chen et al. (2010) identified a heterozygous R315W mutation in a 47-year-old mother and her 26-year-old daughter with HMSN2C and vocal cord paresis; the family had originally been reported by Dyck et al. (1994). Both patients had onset in infancy and developed a relatively severe form of distal muscle weakness and distal sensory loss, as well as short stature. Aharoni et al. (2011) reported a 3-generation family of Ashkenazi/Sephardic Jewish origin with variable expression of HMSN2C due to a heterozygous R315W TRPV4 mutation. Five mutation carriers in 1 family were studied. The proband was a girl who presented at birth with inspiratory stridor, clubfeet, congenital hip dislocation, and knee contractures. She had absent reflexes and bilateral vocal cord paresis requiring tracheostomy. In childhood, she showed delayed motor development, progressive distal amyotrophy and weakness, weakness of the shoulder girdle, scoliosis, and pectus excavatum. Neurophysiologic studies showed an axonal sensorimotor neuropathy. Two of her affected brothers also presented with stridor in infancy and showed a similar phenotype, but without electrophysiologic examination. The mother showed a milder phenotype; she reported being unathletic as a child and having a hoarse voice. In her thirties, she developed slowly progressive fatigue associated with mild distal muscle atrophy in the lower limbs. She had poor reflexes and minimal distal temperature sensitivity. Electrophysiologic studies showed a sensorimotor neuropathy. One mutation carrier in this family was clinically unaffected at age 14 years, although deep tendon reflexes were difficult to elicit. (less)

Auer-Grumbach et al. (2010) reported a large 5-generation family in which 10 individuals with a neuromuscular disease carried the same heterozygous c.943C-T transition in exon 6 of the TRPV4 gene, resulting in an arg315-to-trp (R315W) substitution. Four patients had hereditary motor and sensory neuropathy type IIC (HMSN2C; 606071), 1 had distal hereditary motor neuropathy, type VIII (HMND8; 600175), and 2 had scapuloperoneal spinal muscular atrophy (SPSMA; 181405). Inheritance was autosomal dominant. The R315W mutation was also identified in an unrelated family in which 6 members had HMSN2C (McEntagart et al., 2005). The mutation was not found in 304 control individuals. The R315W mutation occurred at the outer helices of the ANK4 and ANK5 domains in the N-terminal cytoplasmic domain. In vitro functional expression studies in HeLa cells showed that the mutant protein formed cytoplasmic aggregates and had reduced surface expression. In cotransfection studies, both mutant and wildtype proteins were detected in cytoplasmic aggregates. Mutant TRPV4 cells showed an impaired response to stimulus-dependent channel activity. The studies indicated that the mutation interferes with normal channel trafficking and function. Haploinsufficiency was proposed as the most likely underlying mechanism, although a gain of function could not be fully excluded. Chen et al. (2010) identified a heterozygous R315W mutation in a 47-year-old mother and her 26-year-old daughter with HMSN2C and vocal cord paresis; the family had originally been reported by Dyck et al. (1994). Both patients had onset in infancy and developed a relatively severe form of distal muscle weakness and distal sensory loss, as well as short stature. Aharoni et al. (2011) reported a 3-generation family of Ashkenazi/Sephardic Jewish origin with variable expression of HMSN2C due to a heterozygous R315W TRPV4 mutation. Five mutation carriers in 1 family were studied. The proband was a girl who presented at birth with inspiratory stridor, clubfeet, congenital hip dislocation, and knee contractures. She had absent reflexes and bilateral vocal cord paresis requiring tracheostomy. In childhood, she showed delayed motor development, progressive distal amyotrophy and weakness, weakness of the shoulder girdle, scoliosis, and pectus excavatum. Neurophysiologic studies showed an axonal sensorimotor neuropathy. Two of her affected brothers also presented with stridor in infancy and showed a similar phenotype, but without electrophysiologic examination. The mother showed a milder phenotype; she reported being unathletic as a child and having a hoarse voice. In her thirties, she developed slowly progressive fatigue associated with mild distal muscle atrophy in the lower limbs. She had poor reflexes and minimal distal temperature sensitivity. Electrophysiologic studies showed a sensorimotor neuropathy. One mutation carrier in this family was clinically unaffected at age 14 years, although deep tendon reflexes were difficult to elicit. (less)