Tags
developmental biology, genetics, neurogology, Physical Anthropology, quadrupedalism, tayfun ozcelik, turkey, uner tan, VLDLR
Remember in 2005-06 when there was a whole lot of buzz about the quadrupedal siblings in Turkey? There first was this paper, “Cerebellar hypoplasia and quadrupedal locomotion in humans as a recessive trait mapping to chromosome 17p,” and then there was this paper, “A new syndrome with quadrupedal gait, primitive speech, and severe mental retardation as a live model for human evolution,” which made a big splash… enough of a splash that a NOVA special was made.
John Hawks criticized this all, especially on the merit if this ‘behavior’ is due to genetic mutations, but he also had beef with how the press was handling the implications of these people. I too didn’t like how everyone was calling these modern humans with a syndrome as primitive cavemen, but what can you do?
Of course, as physical anthropologists, we can’t ignore these quadrupeds because they walk on all fours, and some of our closest evolutionary cousins (chimpanzees and gorillas) also walk on all fours. But you can’t say these people reverted back to a more ancestral primate locomotion technique. Chimps and gorillas walk on their knuckles, whereas these people walk plantigrade. Also, they look more strained walking on fours than do our more furry primate brethren, and that makes sense because limb proportions and overall body size of these people still are bipedal in pattern.
Well, it has been pretty quiet since then. We haven’t heard much from the two families in Turkey who walk on all fours, have speech deficiencies, and exhibit hypoplasia of the brain. I think that will all change with this new awesome PNAS paper that just came out recently. The paper, “Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans,” identifies two mutations in the VLDLR gene from members of the family who have this syndrome.
The last author of this new paper, Uner Tan, was actually the guy who published that 2006 paper which got Hawks to say Tan is incorrect in thinking that the language and locomotion disabilities of these quadrupeds in Turkey are genetically linked. Hawks said,
“Human bipedality and human cognition are both highly complex traits involving anatomical, developmental, and behavioral specializations. Each of them involved hundreds, and for cognition I would say thousands, of different genetic changes. There was no small set of macromutations that caused these traits to arise…
….I think it’s really unlikely that a gene that causes cerebellar ataxia was a critical bipedality gene. It may be necessary to walking normally, but it probably (indeed, evidently from the nature of the disorder) is very important to a lot of other things as well. A gene that breaks early brain development is no more likely than other genes to have a specific function role in the development or practice of bipedalism in humans…
…The main point is this: the fact that a gene breaks something doesn’t mean that it was the key gene necessary to create something. Suppose that you want to figure out how a car works. So you look at cars that aren’t working right, and you see what is broken. Now, you will notice that cars run sort of poorly with flat tires, they run with depleted batteries but won’t start, they will run for a bit without motor oil, but then seize up, and so on.
Cerebellar ataxia breaks a whole lot of things. It’s like breaking the crankshaft — the engine might run, but it is going to make a whole lot of noise, and the car isn’t going to move. We may conclude that the crankshaft is necessary for the wheels to move. But does that mean that the crankshaft is the key component of the wheel? Clearly not.
The analogy between cars and organismal development is useful because both systems depend on hierarchical functions. Early things must all work right for later things to develop. When an upstream gene (or part) breaks, it doesn’t mean that downstream things affected by the broken gene were caused by the broken gene.”
Now it seems like Tan et al. have found a gene that affects the development of bipedality and language, as well as a lot of other things. Actually the authors used genome-wide analytic tools to genetically map regions on three different chromosomes that are shared and are responsible for the condition seen in the two different families. Most the most interesting genetic similarity is a homozygoitic 1.3 megabase region of chromosome 9. Within this region, lies the gene VLDLR.
VLDLR is a gene that encodes a low density lipoprotein receptor. Its widely found in heart, skeletal muscle, and adipose tissue and thought to function in fatty acid metabolism, bringing in different molecules like enzymes and transporters into the cell. VLDLR has been actually identified as a critical component of the reelin signaling pathway, a cascade of events that develop the central nervous system. So it is not exclusively expressed in heart, muscle, and fat. Any deleterious mutation in VLDLR would ultimately effect how the nervous system is made and how it functions. Since locomotion and language are controlled by the central nervous system, you can begin to see how important VLDLR is. Aside from neural development, the authors hypothesize that VLDLR functions in positioning cells in the brain, and maturing the cerebellum so that bipedalism can function.
The authors decided to hone in on VLDLR. They made a pedigree chart that shows the affected individuals, and sequenced the VLDLR gene from affected individuals in both families. They were able to identify two mutant alleles, specific to each family, that deviated with the wild type VLDLR gene. Affected individuals in the first family carried a swap of a cytosine to a thymine in position 769 of the gene. This is a single nucleotide polymorphism (SNP) that caused a nonsense mutation, resulting in a premature stop codon. The second family actually had a deletion of a thymine in position 2339. This is also a single nucleotide SNP. Had this deletion been in 3 bases, carriers of this allele may have had a functioning VLDLR receptor, but since it involved a single base, a frame shift occurred and basically messed up everything downstream. I’ve taken out the chormatogram from the sequencing to show you what the mutations look like:
The authors confirmed the extent of these mutations using qPCR. They were able to show how the early stop and frameshift mutations are both in the part of resultant protein that binds reelin, and ultimately are not able to begin the reelin signal transduction.
This paper is really elegant! It is very simple and powerful. They were able to correlate a phenotype to a mutation in a important gene that affects how the nervous system is developed, and how it functions. Since these people affected by Unertan syndrome have serious neurological disorders, it is a pretty clear genotype-phenotype association. I feel Tan and crew are vindicated from Hawks criticisms.
- Ozcelik, T., Akarsu, N., Uz, E., Caglayan, S., Gulsuner, S., Onat, O.E., Tan, M., Tan, U. (2008). Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans. Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0710010105
- TAN, U. (2006). A NEW SYNDROME WITH QUADRUPEDAL GAIT, PRIMITIVE SPEECH, AND SEVERE MENTAL RETARDATION AS A LIVE MODEL FOR HUMAN EVOLUTION. International Journal of Neuroscience, 116(3), 361-369. DOI: 10.1080/00207450500455330
- Turkmen, S. (2005). Cerebellar hypoplasia and quadrupedal locomotion in humans as a recessive trait mapping to chromosome 17p. Journal of Medical Genetics, 43(5), 461-464. DOI: 10.1136/jmg.2005.040030
No..
The first was the following paper:
Uner Tan (2005).Unertan syndrome: quadrupedality, primitive language, and severe mental retardation; A new theory on the evolution of human mind. Neuroquantology, 2005, issue 4, page 250-255.
There’s a long-ago-described disorder called “VLDLR-associated cerebellar hypoplasia”, previously “Disequilibrium syndrome”.
http://en.wikipedia.org/wiki/VLDLR-associated_cerebellar_hypoplasia
I wonder that’s the difference between this and the Unertan Syndrome and how they may relate.
Uner,
Thanks for clarification. I shoulda researched more and tracked down the first paper. I just posted on what I read and had in my possession.
Anyways, thanks again, I’ll be sure to read your Neuroquantology paper. And also, good job on this PNAS, you and your team of authors made and excellent scientific discovery and presented it in a very clear and concise manner!
Kambiz
CopperKettle,
That’s very interesting, it is no surprise that VLDLRCH, where the VLDLR gene is disrupted, is cause for mental retardation and hypoplasia of the cerebellum. I too wonder then if Unertan Syndrome is unique, that would be very interesting?
As you know the cerebellum integrates sensory perception and motor control. Seems like a immature cerebellum would most certainly have affects on balance and locomotion.
Thanks for the comment, I wonder if Uner Tan and any of the others of this paper have heard of VLDLRCH before and what they think of it? Actually, any physicians, neurologists, out there wanna chime in on if VLDLRCH and Unertan syndrome are the same thing?
Kambiz
Thank you very much Dear Kambiz..
All the best,
Uner
Dear Kambiz:
Turkmen et al. have published the updated article in the Journal of Medical Genetics in 2006 (43: 461-464). This is the real reference, since the first online publication won’t be valid after the publication of the updated article in the journal. For instance our article in online PNAS, won’t be valid after its publication in the Journal “PNAS (USA). Acoordingly, we will use the Journal PNAS in references, not the online paper.
Best,
Uner
Hi, Kambiz —
I think you’re missing my argument. It’s certainly plausible that these ataxia cases have a genetic cause (or causes), and the genes that are involved might be interesting.
But the hypothesis that these genes were themselves involved with the origin of bipedality (or language) requires different evidence. In particular, it requires a comparison with chimpanzees or other hominoids, showing that the human form exhibits functional changes. Even better would be evidence of selection on the gene within the human lineage.
That is what we have for FoxP2, for example — not only is it implicated in the pathological form of SLI, but it is also clearly different between humans and other hominoids, and shows good evidence of selection on the human lineage. And even then, we still don’t know what it does or why it was selected.
A contrary example is FGFR3, some mutations of which cause achondroplasia. This developmental reduction in body size may be compared to the vast increase in body size that evolved during human evolution. But as far as we know, that increase did not involve any adaptive changes to FGFR3, and there is no particular evidence of selection on the gene in the human lineage.
So my point is that studying the pathology is *not* studying the origins of bipedality. There’s no necessary connection between the two, nor is there any expectation that we will learn about one from the other.
I would say that the PNAS paper puts the situation very well — it says in the conclusion that the identification of VLDLR-based pathologies may lead to more insight about the neural mechanisms that maintain gait in humans.
I’m not a specialist, but I’ve partly read John Hawk’s critique of 2006 and so far John’s arguments seem justified to me, and I see no reason why the PNAS paper must refute them. Bipedalism and intelligence are indeed must depend on many genes.
As I understood, there are two genetic loci linked to the syndrome. One gene has been found, and turned out to be the gene linked previously to Disequilibrium syndrome, later renamed VLDLRCH. I will wait for an answer whether some cases of Unertan syndrome might really be “rediscovered” VLDLRCH, which is described in Hutterite communities, for example. There must exist descriptions of Hutterite cases, why not compare them with Turkish families’ members affected by the syndrome. It is interesting what will be the second gene, that on the chromosome 17..
I was interested in VLDLRCH because VLDLR, along with ApoER2, is one of the reelin receptors, and reelin brain levels are reported to be consistently low in cases of schizophrenia and psychotic bipolar disorder. Reading about molecular mechanisms of schizophrenia is a kind of my hobby. I was adding some info to the reelin-related wikipedia pages now and then, and only yesterday struck upon the quaint “Unertan syndrome”.
P.S. I’ve found that in the Tan’s paper “Unertan syndrome: a case series demonstrating human devolution” the differences between UTC and DES\VLDLRCH are indeed discussed:
Thank you very much Dear CopperKettle for your excellent summary on differences between UTS and DES.
All the best,
Uner
Still Reelin’ from all these infos. Splendidly written article. Homozygosity in chr 9 raises the doubt that these may be due to consanguineous relationships involved, in addition to frame-shift or non-sense mutations.
It seems that reelin signalling pathway, that gets modified via the instruction of VLDLR, will reveal many secrets of embryology, establishing “ontogeny repeats phylogeny” in a brand new light.
There are reports of feral children, raised by animals, who have also been found walking on all fours. Is it possible the Turkish individuals were simply neglected at a crucial developmental stage? Isn’t walking upright an activity that is learned?
I’m glad to see this discussion developing. Here, below, is a copy of a message I’ve sent to the lead author of the PNAS paper.
Best, Nicholas Humphrey
**
As you will know, I and my colleagues from England published an early account of the syndrome in the Ulas family (your family B) in 2005.
http://www.lse.ac.uk/collections/CPNSS/pdf/DP_withCoverPages/DP77/DP7705.pdf
Since then I have been involved with Stefan Mundlos in researching your family A which was first “discovered” by us as a result of the BBC TV documentary. We have also more recently researched a family with a similar syndrome in Iraq. A report of the Iraqi family “Life on all fours” appeared in the London Times in November last year.
http://www.timesonline.co.uk/tol/life_and_style/health/article2671426.ece
We (Mundlos and his team) have a paper in press in EJHG which describes our own findings with your family A. I’m glad to say we are in complete agreement with you about the genetics of family A. We will shortly also be publishing our genetic findings with the Iraqi family, in whom we have found yet another different mutation.
Our own conclusions about the origins of quadrupedal locomotion are different from yours. We see it as an adaptive compensation for problems with balance (caused by congenital cerebellar hypoplasia in some cases , or in other cases that we know of by later-onset conditions such as Parkinsonism). We do not believe that so-called “Unertan syndrome” is a useful diagnostic category, or that it has the scientific significance that Tan wants to attach to it (evidence of “backwards evolution”).
However we still regard these cases as being of great interest from the point of view of human development. They provide “text-book cases” of how genes and environment interact to determine the phenotypic outcome, and of how disparate influences can lead to a convergence on an unusual “attractor state” — namely, in this case palmigrade quadrupedalism. We also think that the fact that palmigrade quadrupedalism is still in modern humans an attractor state may tell us something about human pre-history (perhaps our ancestors were indeed palm-walkers rather than knuckle-walkers).
Our Reply to Herz et al. and Humphrey
et al.: E32–E33 PNAS June 10, 2008 vol. 105 no. 23
Genetic heterogeneity of cerebellar hypoplasia with quadrupedal locomotion
Mutations in the very low-density lipoprotein receptor VLDLR are responsible for cerebellar hypoplasia with quadrupedal gait (1). The most likely mechanism leading to this phenotype is that VLDLR deficiency in the brain at a key stage of development precludes the normal formation of neural
structures critical for gait. Quadrupedal gait is an integral part of VLDLR-associated cerebellar hypoplasia syndrome in these families (1, 2). It is not necessary to invoke an ‘‘epiphenomenon’’
or ‘‘unfavorable environmental conditions’’ to explain the phenotype (3), but rather simply considering clinical heterogeneity in the context of genomic understanding of complex traits is sufficient. Disequilibrium syndrome was first described by the Swedish neuropediatrician Bengt Hagberg and colleagues (4) as a form of cerebral palsy characterized by a variety of congenital
abnormalities. Subsequently, Schurig et al. (5) described, in the North American Hutterite population, inherited cerebellar disorder with mental retardation, the genetic basis of which
proved to be homozygous deletion of the VLDLR gene and the adjacent noncoding LOC401491 sequence (6). Based on the phenotypic similarities of the Swedish and Hutterite patients, the acronym DES-H [disequilibrium syndrome-Hutterites, Online Mendelian Inheritance in Man (OMIM) accession no. 224050] was adopted for this syndrome (6).
Our results (1) and those of others (7) extend these findings to different VLDLR mutations leading to cerebellar hypoplasia and related disequilibrium features, including in some families bipedal gait (5, 6), in other families quadrupedal gait
(1, 8), and in another family ‘‘gait ataxia’’ (7). Additional kindreds with disequilibrium syndrome and quadrupedal gait have been described in Brazil (9) and Iraq (10). It will be interesting to know whether mutations responsible for the phenotype
in these families lie in the VLDLR gene or in one
of the other loci linked to this genetically heterogeneous phenotype (1).
The comments of Humphrey et al. (11) address three fundamental features of genomic analysis of human traits: allelic heterogeneity, genotype–phenotype correlations, and variable expression.
Allelic heterogeneity—the expression of the same phenotype due to different mutations in a gene—is characteristic of virtually all human genetic disease. For example, homozygosity for any of 300 different mutations in the LDL receptor leads to hypercholesterolemia. It was to be expected, therefore, that in different families different mutations in VLDLR would lead to a phenotype comprising cerebellar hypoplasia with quadrupedal gait. It would not be expected that quadrupedalism
would be present only in the presence of one ‘‘specific mutation.’’ The converse observation, of a correlation between genotype and phenotype, is also characteristic of inherited human disease. Different mutations in the same gene frequently lead
to different clinical phenotypes. Contrary to the statement of Humphrey et al. (11), the Hutterite families in North America and families A and D in Turkey do not carry ‘‘the same homozygous
mutation.’’ The Hutterite mutation is a complete
genomic deletion of VLDLR; the mutations in Turkish families A and D are, respectively, a nonsense mutation and a single-base-pair deletion leading to a frame shift in VLDLR. It is not surprising, therefore, that features of the cerebellar
hypoplasia syndrome, including presence or absence of quadrupedal walking, differ among families with different mutations in the gene.
Third, variable expression of a phenotype is frequently observed even among persons with the same mutation in a critical gene. Variable expression may be due to differences in genetic background of the individual, to differences in environmental
exposures, or to chance. Among affected individuals
in families A and D, none displays exclusively bipedal locomotion; two affected individuals can walk bipedally for short distances but prefer quadrupedal locomotion (1, 8).
Finally, the use of a walking frame to assist bipedalism in affected individuals (12) does not demonstrate that the cause of quadrupedalism was ‘‘local cultural environment.’’ Wearing
eyeglasses assists persons with myopia. Should we then conclude that near-sightedness is caused by ‘‘local cultural environment’’?
Some descriptions by the press of Turkish families with cerebellar hypoplasia and quadrupedal gait have portrayed the affected individuals as doomed to quadrupedal gait by the religious beliefs of their parents (13). We hope that future descriptions of these families will conform to standards reflected
in recent genomic analyses of their disorder.
Tayfun Ozcelik*†‡, Nurten Akarsu§¶, Elif Uz*, Safak Caglayan*, Suleyman Gulsuner*, Onur Emre Onat*, Meliha Tan, and Uner Tan**
*Department of Molecular Biology and Genetics, Faculty of Science,and †Institute of Materials Science and Nanotechnology, Bilkent University, Ankara 06800, Turkey; §Department of Medical
Genetics and ¶Gene Mapping Laboratory, Department of Pediatrics, Pediatric Hematology Unit, Ihsan Dogramaci Children’s Hospital, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey; Department of Neurology, Baskent University Medical
School, Ankara 06490, Turkey; and **Faculty of Sciences, Cukurova University, Adana 01330, Turkey
1. Ozcelik T, et al. (2008) Mutations in the very low-density lipoprotein receptor VLDLR cause
cerebellar hypoplasia and quadrupedal locomotion in humans. Proc Natl Acad Sci USA
105:4232–4236.
2. Tan U (2005) A new theory on the evolution of human mind. Unertan syndrome: Quadrupedality,
primitive language, and severe mental retardation. NeuroQuantology 4:250–255.
3. Herz J, Boycott KM, Parboosingh JS (2008) ‘‘Devolution’’ of bipedality. Proc Natl Acad
Sci USA 105:E25.
4. Hagberg B, Scanner G, SteenM(1972) The dysequilibrium syndrome in cerebral palsy.
Clinical aspects of treatment. Acta Paediatr Scand 61(Suppl 226):1– 63.
5. Schurig V, Van Orman A, Bowen P (1981) Nonprogressive cerebellar disorder with mental
retardation and autosomal recessive inheritance in Hutterites. Am JMed Genet 9:43–53.
E32–E33 PNAS June 10, 2008 vol. 105 no. 23 http://www.pnas.orgcgidoi10.1073pnas.0804078105
6. Boycott KM, et al. (2005) Homozygous deletion of the very low density lipoprotein
receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral
simplification. Am J Hum Genet 77:477–483.
7. Moheb LA, et al. (2008) Identification of a nonsense mutation in the very low-density
lipoprotein receptor gene (VLDLR) in an Iranian family with dysequilibrium syndrome.
Eur J Hum Genet 16:270–273.
8. Turkmen S, et al. (March 26, 2008) Cerebellar hypoplasia, with quadrupedal locomotion,
caused by mutations in the very low-density lipoprotein receptor gene. Eur JHum
Genet, 10.1038/ejhg.2008.73.
9. Garcias GL, RothMG(2007) A Brazilian family with quadrupedal gait, severe mental
retardation, coarse facial characteristics, and hirsutism. Int J Neurosci 117:
927–933.
10. Fletcher M (October 17, 2007) Life on all fours. Times Online. Available at http://www.timesonline.
co.uk/tol/lifeandstyle/health/article2671426.ece.
11. Humphrey N, Mundlos S, Turkmen S (2008) Genes and quadrupedal locomotion in
humans. Proc Natl Acad Sci USA 105:E26.
12. Harrison J, Holt S (2006) The Family That Walks on All Fours (BBC, London).
13. Ahuja A (2007) We’re all made with quadrupedal walking ability. Times Online. Available
at http://women.timesonline.co.uk/tol/lifeandstyle/women/thewaywelive/
article2671044.ece.
Author contributions: T.O., N.A., E.U., S.C., S.G., O.E.O., M.T., and U.T. wrote the paper.
The authors declare no conflict of interest.
‡To whom correspondence should be addressed. E-mail: tozcelik@bilkent.edu.tr.
© 2008 by The National Academy of Sciences of the USA
Ozcelik
Please see the following review article on the Uner Tan syndrome for a more detailed information:
The Open Neurology Journal, 2010, 4, 78-89
1874-205X/10 2010 Bentham Open
Open Access
Uner Tan Syndrome: History, Clinical Evaluations, Genetics, and the
Dynamics of Human Quadrupedalism
Uner Tan*,1
Department of Physiology, Çukurova University, Medical School, 01330 Adana, Turkey
Abstract: This review includes for the first time a dynamical systems analysis of human quadrupedalism in Uner Tan
syndrome, which is characterized by habitual quadrupedalism, impaired intelligence, and rudimentary speech. The first
family was discovered in a small village near Iskenderun, and families were later found in Adana and two other small villages
near Gaziantep and Canakkale. In all the affected individuals dynamic balance was impaired during upright walking,
and they habitually preferred walking on all four extremities. MRI scans showed inferior cerebellovermian hypoplasia
with slightly simplified cerebral gyri in three of the families, but appeared normal in the fourth. PET scans showed a decreased
glucose metabolic activity in the cerebellum, vermis and, to a lesser extent the cerebral cortex, except for one patient,
whose MRI scan also appeared to be normal. All four families had consanguineous marriages in their pedigrees,
suggesting autosomal recessive transmission. The syndrome was genetically heterogeneous. Since the initial discoveries
more cases have been found, and these exhibit facultative quadrupedal locomotion, and in one case, late childhood onset.
It has been suggested that the human quadrupedalism may, at least, be a phenotypic example of reverse evolution. From
the viewpoint of dynamic systems theory, it was concluded there may not be a single factor that predetermines human
quadrupedalism in Uner Tan syndrome, but that it may involve self-organization, brain plasticity, and rewiring, from the
many decentralized and local interactions among neuronal, genetic, and environmental subsystems.
Having found a family of parents with 11 childrn all with Uner Tan syndrome and living in the mountains in Morocco i have bee trying to find out what to do for the younger children such as age 5.3 or 1yrs old. I am not a medical professional by I have tried my level best to get the local authorities, the media and even the King of Morrocco to intervene in order to find a solution a the family has no means of ressources nor even water and the father till not too long ago used to go get it by travelling 3hrs a day.Can any medictaion,physiotherapy or other treatment help.These children are also for some deaf+dumb and even blind. Thank you for your help.
Regards,
Said and Sonal