Table 2.
Systematic review of published literature of TRPV4 mutations associated with mixed neuropathy and skeletal dysplasia manifestations.
| Amino acid | Protein domain | Mutation | Patients (n) | Families (n) | Inheritance | Sex (male, n) | Mean age at onset in years (range) | Origin | Neuropathy phenotype | Progressive (yes) | Proximal UL motor | Distal UL motor | Proximal LL motor | Distal LL motor | Sensory symptoms | Vocal cord involvement | Diaphragmatic involvement | Scapular winging | Decreased CMAP UL | Decreased CMAP LL | Decreased SAP UL | Decreased SAP LL | Denervation | Skeletal dysplasia diagnosis | Additional features | Reference |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| G78W | N‐terminal | NR | 1 | 1 | De novo | 1/1 | 0 (congenital) | NR | CDSMA | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | MD | Contractures, fetal akinesia syndrome | 21 |
| R186Q | ARD1 | 557G > A | 1 | 1 | AD | NR | <5 | France | CSMAA | 1/1 | 1/1 | 1/1 | 1/1 | 1/1 | 0/1 | 0/1 | 0/1 | 0/1 | 1/1 | 1/1 | 0/1 | 0/1 | 1/1 | MD/brachyolmia | ‐ | 10 |
| A217S | ARD2 | 649G > T | 1 | 1 | De novo | 0/1 | 0 (congenital) | Argentina | SHSMA | NR | 1/1 | 1/1 | 1/1 | 1/1 | 0/1 | 0/1 | 0/1 | 1/1 | 0/1 | 0/1 | 0/1 | 0/1 | 1/1 | SMD‐K | Facial palsy, hyperlaxity | 22 |
| R232C | ARD2 | 694C > T | 3 | 2 | AD, de novo | 1/1 | 3 (0–5) | Greece, Italy | CDSMA (1/3), CMT2C (2/3) | 2/2 | ||||||||||||||||
| (1 NR) | 1/3 | 3/3 | 3/3 | 3/3 | 2/3 | 3/3 | 1/3 | 0/3 | 1/2 | 1/2 | 1/2 | 1/2 | 2/2 | MD/ brachyolmia | ‐ | 10,23 | ||||||||||
| R269H | ARD3 | 806G > A | 4 | 4 | AD, de novo | 1/3 | 1.3 (0–5) | Netherlands, France, Italy, USA | CDSMA/ CSMAA (3/4), SPSMA (1/4) | 3/3 (1 NR) | 2/4 | 2/4 | 2/4 | 4/4 | 1/4 | 1/4 | 1/4 | 2/4 | 1/2 | 1/2 | 0/3 | 0/3 | 4/4 | FDAB, MD/brachyolmia | Spina bifida | 10,24,25 |
| R269C | ARD3 | 805C > T | 1 | 1 | De novo | 1/1 | 0 (congenital) | UK | SPSMA | NR | 1/1 | 0/1 | 1/1 | 1/1 | 0/1 | 0/1 | 0/1 | 1/1 | NR | NR | NR | NR | 1/1 | MD | Dysphagia | 27 |
| K276E | ARD3 | NR | 1 | 1 | De novo | 1/1 | 0 (congenital) | Algeria | CDSMA | NR | NR | NR | 1/1 | 1/1 | NR | NR | NR | NR | NR | NR | NR | NR | 1/1 | MD | Contractures, fetal akinesia syndrome | 21 |
| E278K | ARD3 | 832G > A | 1 | 1 | AD | 0/1 | 0.5 | Korea | CMT2C | 1/1 | 0/1 | 0/1 | 1/1 | 1/1 | 0/1 | 0/1 | 0/1 | 0/1 | NR | 1/1 | NR | 0/1 | 1/1 | SMD‐K | ‐ | 22 |
| R315W | ARD4 | 943C > T | 1 | 1 | De novo | 0/1 | 1.5 | USA | CMT2C | 1/1 | 0/1 | 1/1 | 1/1 | 1/1 | 1/1 | 0/1 | 0/1 | 0/1 | NR | 1/1 | NR | 1/1 | 1/1 | SMD‐K | ‐ | 28 |
| R316C | ARD4 | 946C > T | 2 | 1 | AD | 2/2 | 2 (0–4) | USA | SPSMA | 2/2 | 2/2 | 2/2 | 2/2 | 1/2 | 0/2 | 0/2 | 0/2 | 1/2 | NR | NR | NR | NR | 2/2 | NR | Oculomotor abduction, facial palsy | 29 |
| E435K | pre‐TM1 | 1303G > A | 1 | 1 | De novo | 0/1 | 0 (congenital) | USA | Arthrogryposis multiplex | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | MD | Tethered cord, thrombocytosis | 30 |
| S542Y | Ligand binding | 1625C > A | 6 | 1 | AD | 2/6 | 11.5 (1–25) | USA | CMT2C | NR | 1/6 | 0/6 | 1/6 | 4/6 | 2/6 | 4/6 | 1/6 | 0/6 | 1/6 | 3/6 | NR | NR | 3/6 | MD | Sleep apnea, pupillary abnormality | 31 |
| L619P | TM5 | 1856_1857delinsCT, 1856 T > C | 2 | 2 | De novo | 0/2 | 1.5 (0–3) | Netherlands, Brazil | CMT2C, CDSMA | 2/2 | 1/2 | 2/2 | 1/2 | 1/2 | 0/2 | 2/2 | 1/2 | 0/2 | 1/1 | 1/1 | NR | NR | NR | Brachyolmia | *Central sleep apnea, tethered cord | 32 |
| V620I | TM5 | 1858G > A | 1 | 1 | De novo | 0/1 | 6 | Croatia | CMT2C | 1/1 | 0/1 | 0/1 | 0/1 | 1/1 | 0/1 | 0/1 | 0/1 | 0/1 | 0/1 | 1/1 | 0/1 | 1/1 | 1/1 | Brachyolmia | ‐ | 11 |
| T740I | C‐terminal | NR | 2 | 1 | De novo | NR | 0 (congenital) | NR | CDSMA | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | MD | Contractures, fetal akinesia syndrome | 21 |
| W785C | C‐terminal | 2355G > T | 5 | 1 | AD | 2/5 | 2.8 (2–4) | China | CDSMA | 5/5 | 0/5 | 0/5 | 5/5 | 5/5 | 0/5 | 0/5 | 0/5 | 0/5 | 0/2 | 0/2 | NR | NR | 2/2 | NR | Scaly skin | 33 |
| P799R | C‐terminal | 2396C > G | 1 | 1 | De novo | 0/1 | 13 | Japan | CMT2C | 1/1 | 0/1 | 0/1 | 1/1 | 0/1 | 0/1 | 0/1 | 0/1 | 0/1 | NR | NR | NR | NR | NR | SEMD‐M | ‐ | 22 |
| E840K, N833S | C‐terminal | 2518G > A 2498A > G | 2 | 1 | Compound heterozygous | 1/2 | 0.3 (0.3–0.3) | Canada | CMT2C | 2/2 | NR | NR | NR | NR | NR | NR | NR | NR | 2/2 | 2/2 | 2/2 | 2/2 | NR | NR | Sensorineural hearing loss, retinopathy, intellectual disability | 34 |
Footnotes: Genetic, epidemiological, clinical, and electrophysiological characteristics are reported for each individual mutation. Data are expressed as fractions of observed cases/reported cases.
Abbreviations: CDSMA, congenital distal spinal muscle atrophy; SPSMA, scapuloperoneal spinal muscle atrophy; SHSMA, scapulo‐humeral spinal muscular atrophy; CSMAA, congenital spinal muscular atrophy and arthrogryposis; MD, metatropic dysplasia; SMD‐K, spondylometaphyseal dysplasia, Kozlowski type; SEMD‐M, spondyloepimetaphyseal dysplasia, Missouri type; FDAB, familiar digital arthropathy brachydactyly; NR, not reported; AD, autosomal dominant; UL, upper limbs; LL, lower limbs; CMAP, compound muscle action potential; SAP, sensory action potential. *multiple additional features were reported, including neurogenic bladder, pigmentary retinopathy, tongue fasciculations, thoracic meningomyelocele with syrinx, sensorineural and mixed hearing loss, left facial palsy, arthrogryposis multiplex congenital.