This Month in The Journal

Abstract

Two types of acromelic dysplasia, geleophysic dysplasia (GD) and acromicric dysplasia (AD), are clinically defined disorders each of which is characterized by extreme short stature with bone and joint abnormalities and distinct facial features. In this issue, Le Goff and colleagues use exome sequencing and subsequent Sanger sequencing to identify mutations in FBN1 in individuals with GD and in those with AD. The involvement of FBN1disruption in these growth disorders is particularly interesting because mutations in the gene are known to cause Marfan syndrome for which tall stature is a defining phenotype. How can disruption of the same gene lead to such different clinical presentations? The authors analyze their mutations in an effort to start to address that question. Of particular note is that each of the 16 mutations identified in individuals with GD or AD is located in the region that encodes the TGF-β binding protein like 5 (TB5) domain. In patient cells, these mutations disrupt microfibril formation and organization and enhance TGF-β signaling. TGF-β activation is also seen in Marfan syndrome, so additional regulatory factors must be involved in the differential mutation effects. One player may be ADAMTSL2. The gene encoding ADAMTSL2 has been shown previously to be mutated in individuals with GD, and here, Le Goff et al. demonstrate that FBN1 and ADAMTSL2 interact directly with each other. Additional analyses will contribute to our growing interest! Posttranslational modifications (PTMs) are changes made to proteins after translation. PTMs come in many forms and provide tissue and temporal diversity to proteins. Presumably, this diversity results in specialized function not provided by the amino acid sequence alone. Acetylation is one such PTM. Although 80%–90% of human proteins have been found to be modified via N-terminal acetylation, remarkably little is known about the enzyme complexes completing this task or the impact of this type of modification. N-acetyltransferases are enzymes that transfer acetyl groups (CH3CO) from acetyl-CoA to arylamines (including amino acids). The NatA complex is one major N-acetyltransferase complex found in humans. It is composed of a catalytic subunit, ARD1 (encoded by NAA10), and an auxiliary subunit, either NATH (encoded by NAA15) or NMDA receptor regulated 1 like (encoded by NAA16). NatA is thought to play a role in cancer progression and organisms (including flies and worms) lacking the catalytic subunit do not survive. In this issue, Rope and colleagues identify the same NAA10 mutation in two independent and unrelated families presenting with premature aging and other symptoms of what appears to be a new lethal syndrome. Although the exact modifications affected by this mutation are yet to be determined, this study highlights the importance of PTM, specifically N-terminal acetylation, in health and development. The study also demonstrates the utility of a new tool, VAAST, that can be used to prioritize variants found through exome sequencing. We're getting pretty good at doing a whole lot of sequencing, but how well can we determine whether rare variants identified via sequencing are associated with a phenotype? Those developing the methodology to perform such analyses have been working hard to keep pace with the explosion of technological advancements. Many of the first series of programs to deal with rare variants combine together the rare variants found in a region in order to establish that variation within that region is associated; a single variant found in a very small number of individuals isn't enough to produce a significant signal, but assessing several such signals together could establish an association with a functional unit disrupted by a diverse set of variants. These approaches are promising, but one limitation of some of the early methods is that if some variants in a region increase risk and other decrease risk, these signals will cancel each other out. Now, the next round of methods is focusing on combining signals from variants within a region while accommodating the fact that the variants may have effects in opposite directions. In this issue, Wu and colleagues present their sequence kernel association test (SKAT) that accomplishes this goal and that can be used to test for association between rare and common variants with both qualitative and quantitative phenotypes. Throughout history, human exploration, migration, conquest, and collaboration have resulted in the mingling of genetically distinct populations. Studying the way in which genetic regions are arranged in the resultant admixed populations can not only provide insight into the demographic history of the people, but can also contribute to an understanding of how variants within those regions may be associated with traits and diseases. When two ancestral populations are mixed together, large sections of DNA will remain intact in the subsequent generations. As time passes, the length of these regions will be shortened by recombination, but if the admixture event is recent enough, the extended linkage disequilibrium (LD) of these pieces of DNA can be used as a tool in mapping genetic associations. In this issue, Narang and colleagues and Shah and colleagues report their independent analyses of the genetic structure of the Siddis people who live in Western India. Previous work had suggested that the Siddis derived their ancestry from India, Africa, and Portugal, but additional work was needed for clarifying the exact populations that contributed to the Siddis and the timing of the admixture. Their findings support that the ancestral African contribution to the Siddis came from sub-Saharan Bantu-speaking African slaves brought to India by the Portuguese. In addition, the groups demonstrate that the admixture event in the Siddis was recent enough and the extended regions of LD are long enough that the population is likely to serve as an important resource for admixture mapping. Typically, when we think of genetic alterations, single-nucleotide polymorphisms (SNPs), common variants that do not significantly (if at all) alter protein structure or function, and point mutations, changes that result in altered protein and disease, spring to mind. However, trinucleotide repeat number is another common variation, one that is only tolerated to a certain point. Since the early 1990s, when fragile X syndrome was found to be caused by an expansion of the CGG trinucleotide repeat, more attention to these genetic expansions has been paid and more diseases and syndromes have been attributed to expanding nucleotide repeats. CAG, encoding for glutamine, is the most common trinucleotide repeat. Thus, most trinucleotide repeat diseases can be considered polyglutamine diseases. These include Huntington disease and several different spinocerebellar ataxias (SCAs). Trinucleotide expansion disorders not encoding glutamine are grouped together as non-polyglutamine diseases. These include additional neurological conditions such as Friedreich ataxia, myotonic dystrophy, and additional forms of SCA. In this issue, Kobayashi and colleagues identify yet another ataxia, SCA36, caused by nucleotide repeat expansion. Instead of the typical trinucleotide repeat, SCA36 is caused by expansion of a hexonucleotide repeat. Another distinctive feature is that the repeat is located in a noncoding region of NOP56. The authors show that the disease is probably caused by a gain of function of RNA foci, as is thought to be the case for other SCAs. While anticipation, whereby symptoms of disease appear earlier in later generations of the affected, does not appear to apply to SCA36, we do anticipate an expanding interest in this type of genetic alteration.