The authors wanted to investigate whether additional, more severe, mutations in the 11-cis retinol dehydrogenase gene might be responsible for more severe forms of hereditary retinal diseases.
But in the new study, published in today's issue of Cell, a team of geneticists led by Bruce Baker of Stanford University, Jeff Hall of Brandeis University, Barbara Taylor of Oregon State University, and Steve Wasserman of the University of Texas Southwestern Medical Center in Dallas show that males with more severe mutations aren't just indiscriminate, but sexless.
One hypothesis is that more severe mutations might cause embryonic lethality and have hitherto remained undetected.
More severe mutations in SCN2A are extremely rare, causing febrile and afebrile seizures 66 and refractory epilepsy with intellectual disability.
More severe mutations in NEMO result in incontinentia pigmenti, an ectodermal dysplasia without immunodeficiency that presents exclusively in females.
150 The onset is reported to be somewhat earlier, especially in carriers of the more severe mutations, eg, L444P.
Interestingly, the symptoms of this particular patient were indistinguishable of those who had more severe mutations leading to complete loss of Tks4 protein synthesis [ 9].
Altogether, as only hypomorphic mutations are present in males, it seems that more severe mutations, such as the p. (Val107Phe) variant, in hemizygous state might lead to an early intrauterine fetal death, which escapes analytical capabilities.
Assuming the latter, c.428delG KIAA0586 could represent a hypomorphic allele that increases susceptibility to develop JBTS, with more severe mutations required either in trans (in heterozygous carriers, as in most patients reported by Bachmann-Gagescu et al. (2015); Roosing et al. (2015)), or in other genes (in homozygous carriers) for disease manifestation.
Until now, it has not been possible to establish whether these cases are due to more severe mutations or whether they are due to other gene(s) causing the same phenotype, or to the interaction with other intra-erythrocytic defects, such as thalassemia [ 4].
