Six words: Megan Fox in a bubble bath. So why were the internet trolls so busy looking at her thumbs?
Nobody even remembers what the commercial was for… (a Motorola phone, fwiw)
Anyway, there was a little social media fracas after it aired because various internet trolls noticed that a hand model had been used in the close-ups to hold the product.
Apparently the super-sexy starlet’s hands were deemed too unlovely for prime time. Why? What could be so awful, so offensive, so downright ugly that the ad agency had to use a thumb-double (the first and only time I ever want to hear that phrase).
The coolest term to describe it is “digital clubbing,” which sounds like some sort of virtual-world online rave. Among the less-flattering descriptions are “clubbed thumb,” “toe thumb,” “potter’s thumb,” and if we want to get all mean-kid about it, strange, stubby and freakish. Also – inexplicably – “murderer’s thumb.”
Thanks to the internet trolls and some googling, I learned that the technical term for poor Megan’s heinous thumbs is Brachydactyly type D (BDD) : “short and broad terminal flanges of the thumbs.”
Oh yeah, and in case you were wondering why I was so interested… I have them too.
Brachydactyly just means “short digits.” There are multiple types which can be classified based on which fingers and/or toes are affected, how severely they are affected, and whether it is part of a larger syndrome or not. And, of course, on their genetics.
The first clinical descriptions of BDD came out nearly a century ago, in 1923 and 1924. Another one from the Journal of Heredity (1934) could be from Maleficient’s Top 10 List of Curses: “Four generations of short thumbs.” In Japan, this brachydactyly is not rare, and is called Mamushi-yubi (a viper) or Shamoji-yubi (a flat rice paddle used in Japanese cooking). Viper thumbs. Awesome.
A couple of thumbnail images ….
About 3/4 of BDD cases are bilateral, but it can be unilateral – one of my cousins has a unilateral case, with one affected and one normal thumb (hi cuz!). There are other documented instances of unilateral cases and bilateral cases within the same family. The earliest reports stated that inheritance is autosomal dominant and penetrance is complete in females and incomplete in males. But, there is at least one report of a family with incomplete penetrance in a female, where an unaffected woman had a father who was bilaterally affected and a daughter and granddaughter who were unilaterally affected (on opposite thumbs, no less).
In my case, neither of my parents has BDD. Even though my affected cousin is related on my mom’s side, our mutual grandparents and uncles aren’t affected either. So I suppose it’s possible that both my case and my cousin’s are coincidental new mutations. I must be a heterozygote, however, because my daughter’s thumbs are normal.
Now, about the genes.
Obviously any BDD candidate gene would have to be important in embryonic body patterning and bone development. Homeobox (Hox) genes fit the bill perfectly: transcription factors active early in embryogenesis, encoding positional information on the body axis and specifying domains in developing limbs.
(Side note: If I ever write a comic book, I’m totally naming the superheroes after Drosophila Hox genes: Ultrabithorax and Antennapedia. Human Hox genes only got numbers and letters.)
In humans, there are four homeobox gene clusters (A-D) located on 4 different chromosomes (7, 17, 12, 2). The clusters originated from a quadruplication of the same initial set of 13 genes but then each cluster lost one or more genes so now no two clusters are the same. As you would expect, the genes are all in the same order within each cluster, with A1-D1 on the 3’ end and A13-D13 on the 5’ end.
In lab mice, genetic manipulation of the 5’ genes in clusters A and D screws up limb development, including the size, shape and number of the bones. So, because Hox genes are so highly conserved across species, it’s not too surprising that mutations in HOXA13 and HOXD13 cause limb malformation syndromes in humans as well.
A bunch of different types of mutations have been found in the human HOXD13 gene. Expansions in the poly-alanine region cause the protein to clump up in the cytoplasm, and nonsense/frameshift mutations truncate the protein. Those mutations may have a dominant negative or haploinsuffiency effect because the full-length protein is not in the nucleus doing its job correctly.
Missense mutations probably alter the function of the protein rather than wiping it out.
HOXD13 is the only gene linked to BDD so far, but the families with the mutations didn’t have “pure” BDD like Megan and me. The lab discovered two missense mutations in the homeodomain (Ser308Cys and Ile314Leu), but some of the type D-affected family members had type E too (in other words, additional affected fingers and/or toes besides the tip of the thumb). The Ile314Leu was found in 3 British families, and since my cousin and I have British parents this might be our mutation too (if our BDD is actually hereditary instead of spontaneous). In crystal structures, that Ile residue appears to be part of the DNA-binding region in the homeobox, so it’s likely to be important.
Even though Ile to Leu is a very conservative substitution (biochemically speaking), there is evidence that it affects HOXD13 protein function. In keeping with the idea that missense mutations can alter rather than destroy the protein’s function, the Ile314Leu mutant protein binds more tightly to the 5’ -TTAC-3’ sequence but less tightly to 5’ -TTAT-3’ compared to wildtype protein. That means it might be controlling genes with the TTAT regulatory sequence more than it is supposed to, or not controlling the TTAC-containing genes as tightly as it should.
That’s kind of cool because it means the mutation conferred a function to HOXD13 that it didn’t have before. That’s called a gain-of-function mutation. A different mutation a few positions down in the homeobox domain, Glu317Lys, also causes limb malformations in humans and changes the DNA binding characteristics of HOXD13 so that it behaves more like another transcription factor, PITX1.
By now, I’m so curious about this I may try to get my HOXD13 gene sequenced. I found a company, genedx.com, that offers the test. Stay tuned. Maybe Megan will do it with me.
PS, if you’re feeling left out because your hands are normal, you can always order an extra finger (ring):
Facebook group [link]
Sayles, L. P., Jailer, J. W. Four generations of short thumbs. J. Hered. 25: 377-378, 1934.
Mutations:
Missense mutations in the homeodomain of HOXD13 are associated with brachydactyly types D and E. (2003) Am J Hum Genet. 72(4):984-97. [link]
Distinct global shifts in genomic binding profiles of limb malformation-associated HOXD13 mutations. Genome Res. 2013 Dec; 23(12): 2091–2102. [link]