Essentially, this article demonstrates the clinical importance of genetics and of finding the rare people interested in your gene.
Genetic testing has implications for treatment.
1) The physician expected "patient one" to respond to acetazolamide based on the testing but she did not. This study demonstrates the process in an animal model. Why there are hints, the study doe not definitively explain why this happens.
Nature still has surprises.
2) Loss of function changes lead partial restoration of function.
Im the 17th author (aka way down the evolutionary ladder of intelligence here... or qualified to make coffee for this group of geneticists).
PLoS Genet. 2017 Jul 24;13(7):e1006905. doi: 10.1371/journal.pgen.1006905. [Epub ahead of print]Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.
Luo X1, Rosenfeld JA1, Yamamoto S1,2, Harel T1,3, Zuo Z1, Hall M4, Wierenga K4, Pastore MT5, Bartholomew D5, Delgado MR6, Rotenberg J7, Lewis RA1,3,8,9, Emrick L1,8, Bacino CA1, Eldomery MK1,3, Coban Akdemir Z1,3, Xia F1, Yang Y1, Lalani SR1, Lotze T8, Lupski JR1,3,8,9, Lee B1, Bellen HJ1,2,10, Wangler MF1,2; Members of the UDN. Author information
1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
2 Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX.
3 Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
4 University of Oklahoma Health Sciences Center, Oklahoma City, OK.
5 Nationwide Children's Hospital & The Ohio State University, Columbus, OH.
6 Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center andTexas Scottish Rite Hospital, Dallas, TX.
7 Houston Specialty Clinic, Houston, TX.
8 Department of Pediatrics, Baylor College of Medicine, Houston, TX.
9 Texas Children's Hospital, Houston, TX.
10 Howard Hughes Medical Institute, Houston TX.
Dominant mutations in CACNA1A, encoding the α-1A subunit of the neuronal P/Q type voltage-dependent Ca2+ channel, can cause diverse neurological phenotypes.
Rare cases of markedly severe early onset developmental delay and congenital ataxia can be due to de novo CACNA1A missense alleles, with variants affecting the S4 transmembrane segments of the channel, some of which are reported to be loss-of-function.
Exome sequencing in five individuals with severe early onset ataxia identified one novel variant (p.R1673P), in a girl with global developmental delay and progressive cerebellar atrophy, and a recurrent, de novo p.R1664Q variant, in four individuals with global developmental delay, hypotonia, and ophthalmologic abnormalities.
Given the severity of these phenotypes we explored their functional impact in Drosophila. We previously generated null and partial loss-of-function alleles of cac, the homolog of CACNA1A in Drosophila. Here, we created transgenic wild type and mutant genomic rescue constructs with the two noted conserved point mutations.
The p.R1673P mutant failed to rescue cac lethality, displayed a gain-of-function phenotype in electroretinograms (ERG) recorded from mutant clones, and evolved a neurodegenerative phenotype in aging flies, based on ERGs and transmission electron microscopy.
In contrast, the p.R1664Q variant exhibited loss of function and failed to develop a neurodegenerative phenotype.
Hence, the novel R1673P allele produces neurodegenerative phenotypes in flies and human, likely due to a toxic gain of function.
Full article is here.