Table 1.
SREBP pathway-associated diseases and phenotypic overlap
| Phenotypes |
||||||
|---|---|---|---|---|---|---|
| Disease | Gene | Eye | Bone | Hair | Skin | Other |
|
| ||||||
| HMD (MIM# 158310) | SREBF1 (MIM# 184756) | Cataracts, blindness, photophobia | Alopecia | Psoriatic lesions, keratosis, impaired cell junctions | Periorificial mucosal lesion, recurrent infection | |
| IFAP2 (MIM# 619016) | SREBF1 | Photophobia | Sparse or absent hair | Ichthyosis follicularis | ||
| SEDKF (MIM# 618392) | MBTPS1 (MIM# 603355) | Cataracts | Skeletal anomalies, short stature | |||
| IFAP1 (MIM# 308205) | MBTPS2 (MIM# 300294) | Photophobia | Short stature | Sparse or absent hair | Ichthyosis follicularis | Seizures |
| OS (X-linked; MIM# 300918) | MBPTS2 | Digit constriction | Alopecia | Periorificial keratotic plaques | ||
| Osteogenesis imperfecta Type XIX (MIM# 301014) | MBTPS2 | Osteopenia, fractures, short stature, scoliosis | ||||
| KFSDX (MIM# 308800) | MBTPS2 | Photophobia, corneal dystrophy | Progressive cicatricial alopecia | Widespread keratosis pilaris | ||
| Individual 1 |
SREBF2 p.(R519H) |
Photophobia, cranial nerve palsy, ocular motor apraxia, optic nerve hypoplasia, strabismus, myopia | Short stature | Scarring alopecia | Scaly skin, recurrent skin infection, plantar keratitis, abnormal nails | Global impairment, dilated ventricles, periventricular nodular heterotopias, leukomalacia, hippocampal atrophy, small cerebellum, seizures |
| Individual 2 |
SREBF2 p.R519G) |
Optic nerve and chiasm atrophy | Chondrodysplasia punctata (resolved), rhizomelic short stature with an epimetaphyseal dysplasia, unilateral postaxial polydactyly | Alopecia | Scaly and thick skin, skin lesions and callouses in areas of friction | Global impairment, dilated ventricles, subependymal heterotopia, polymicrogyria |
Pathogenic variants in genes encoding members of the SREBP pathway cause various diseases with substantial overlap in phenotypes observed, including in individuals with hereditary mucoepithelial dysplasia (HMD), ichthyosis follicularis, atrichia, and photophobia (IFAP1&2), Olmstead syndrome (OS), and keratosis follicularis spinulosa decalyans (KFSD). Prior to this study, human disease had not been associated with variations in the SREBF2 gene. This work delineates the role of SREBF2 p.(Arg519) variants that cause a previously unreported disease mediated by inhibition of the protease S1P, which should be known as SREBF2-related dermatologic, neurologic, and skeletal defects.