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transcripts and thus positively influences the SMA phenotype (48, 138). Carrier Detection and Frequency Based on molecular genetic data, the worldwide SMA carrier frequency is 1:51, or 3,795/193,586 (173 and references therein) (see Table 1). All studies included only SMA carriers with one SMN1 copy (1:0 genotype); SMA carriers with two SMN1 copies on one chromosome (2:0) or with a point mutation or small deletion within SMN1 (1:1D) were omitted. In the German population, 4.8% of control individuals had two SMN1 genes per chromosome, and 1.7% of SMA parents carried a subtle SMN1 mutation (48, 183). Consequently, these individuals will not be recognized by a quantitative SMN1 screening analysis and are false negatives. The highest frequency seems to occur in the European population (1:41) and the lowest in the sub-Saharan African population (1:145). Interestingly, a pilot newborn screening study in Germany identified 30 out of 213,276 babies as having homozygous SMN1 deletions, giving an SMA incidence of 1:7,109 and a carrier frequency of 1:42 (175). This carrier frequency is very close to the previously calculated frequency for a smaller number of European individuals (1:41). The first newborn screening in the United States identified 38 out of 1,530 newborns to be SMA carriers (1:40), which is also very close to the European frequency but higher than the reported frequencies for various specific US ethnicities, which range from 1:48 to 1:97 (174). However, the total number of individuals in this US newborn screening is smaller than those in the other studies (173). Modifiers of Spinal Muscular Atrophy in Humans Various modifiers of the SMA phenotype have been found in humans, animal models, and genetic screenings (reviewed in 182, 184). Here, we focus only on positive SMN-independent genetic modifiers found in asymptomatic SMN1-deleted individuals in SMA families. Two modifiers have been reported: overexpression of PLS3 and downregulation of NCALD (67, 129, 142). Both were identified by differential expression analysis comparing the transcriptomes of lymphoblastoid cell lines from homozygously SMN1-deleted asymptomatic and symptomatic family members. The underlying molecular mechanism responsible for the upregulation of PLS3 or downregulation of NCALD is still unsolved. In both cases, long-distance upstream or downstream regulatory elements seem to be the cause (B. Wirth, unpublished data). No variants within the two genes seem to be responsible, making direct genetic testing on the DNA level impossible. SMA animal models including mice, zebrafish, flies, and worms in which PLS3 overexpression was induced either genetically or via AAV9-PLS3, or NCALD was downregulated either genetically or via small interfering RNAs or ASOs, have been shown to rescue or ameliorate the SMA pathology. Importantly, these protective modifiers also helped to reveal impaired endocytosis as the primary mechanism that is disturbed by reduced SMN levels and restored by both modifiers (71, 84, 142). www.annualreviews.org • 25 Years of Spinal Muscular Atrophy Research 241 Annu. Rev. Genom. Hum. Genet. 2020.21:231-261. Downloaded from www.annualreviews.org Access provided by 2600:1700:3c30:a3d0:89dc:b3d1:ac73:5085 on 01/23/22. For personal use only. Invertebrate Vertebrate Genetic screening Pathology Preclinical trial Caenorhabditis elegans Drosophila melanogaster Danio rerio Sus scrofa Mus musculus Macaca fascicularis Survival Growth Motor function (pumping) NMJ morphology Motor function In vivo motor neuron growth, morphology, and pathfinding Testing modifiers Survival Weight gain NMJ morphology Motor function Motor neuron phenotypes Testing modifiers Optimization of therapeutic tools Time and method Optimization of therapeutic tools Time and method Figure 3 Animal models of SMA. The various models have been the pillar of SMA translational research, and each one has unraveled unique aspects of SMA pathophysiology and/or defined the direction of SMA drug development. The boxes summarize the most important informative aspects that each model contributed to in the SMA field. Abbreviations: NMJ, neuromuscular junction;
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