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Proc Natl Acad Sci U S A. May 27, 2008; 105(21): E25.
Published online May 16, 2008. doi:  10.1073/pnas.0802584105
PMCID: PMC2396673

“Devolution” of bipedality

Ozcelik et al. (1) report mutations in very-low-density lipoprotein receptor (VLDLR) that are associated with quadrupedal gait. They propose a pivotal role for VLDLR in the transition from quadrupedal to bipedal locomotion in man. VLDLR is a key regulator of cerebellar development in vertebrates (2). All VLDLR mutations reported to date result in disequilibirium syndrome (DES) with cerebellar hypoplasia and are neuroanatomically indistinguishable (1, 3, 4). In contrast to the Turkish population reported by Ozcelik et al., Hutterites carrying a complete deletion of VLDLR are bipedal (3). Ozcelik et al. hypothesize that the Hutterites are more severely afflicted because of a chromosomal deletion and that this causes loss of motor skills required for quadrupedal locomotion, thereby forcing them to habitually walk upright. Quadrupedal locomotion in individuals with cerebellar hypoplasia has been proposed to define a distinct genetic syndrome of “human devolution” or “reverse evolution” (“Unertan syndrome”) (5).

Clinical, evolutionary, and molecular evidence refutes their hypothesis. Quadrupedal locomotion is more likely an adaptation to the severe truncal ataxia present in all VLDLR-deficient patients, resulting from a combination of uneven, rough surfaces in rural areas, imitation of affected siblings, and lack of supportive therapy. Conclusions about the role of VLDLR in the transition from quadrupedal to bipedal locomotion are uninterpretable and untenable in the presence of such extensive structural cerebellar defects. Quadrupedal gait is thus likely an epiphenomenon caused by neurodevelopmental malformation and ataxia combined with unfavorable environmental conditions and does not define a separate genetic entity. A more informative and appropriate name for VLDLR deficiency in disequilibrium syndrome would be DES-VLDLR.

Footnotes

The authors declare no conflict of interest.

References

1. Ozcelik T, et al. Mutations in the very low-density lipoprotein receptor VLDLR cause cerebellar hypoplasia and quadrupedal locomotion in humans. Proc Natl Acad Sci USA. 2008;105:4232–4236. [PMC free article] [PubMed]
2. Trommsdorff M, et al. Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell. 1999;97:689–701. [PubMed]
3. Boycott KM, et al. Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification. Am J Hum Genet. 2005;77:477–483. [PMC free article] [PubMed]
4. Moheb LA, et al. 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. 2008;16:270–273. [PubMed]
5. Tan U, et al. Unertan syndrome: A case series demonstrating human devolution. Int J Neurosci. 2008;118:1–25. [PubMed]

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