TUBITAK Destekli Projelerden Çıkan Yayınlar Topluluğu
Published January 1, 2011 | Version v1
Journal article Open

Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred

Creators

  • 1. Bilkent Univ, Fac Sci, Dept Mol Biol & Genet, TR-06800 Ankara, Turkey
  • 2. Bilkent Univ, Inst Mat Sci & Nanotechnol, TR-06800 Ankara, Turkey
  • 3. Bilkent Univ, Natl Res Ctr Magnet Resonance, TR-06800 Ankara, Turkey
  • 4. Bogazici Univ, Sch Arts & Sci, NDAL Lab, TR-34342 Istanbul, Turkey
  • 5. Ihsan Dogramaci Childrens Hosp, Dept Pediat Neurol, TR-06100 Ankara, Turkey
  • 6. Hacettepe Univ, Fac Med, Dept Neurol, TR-06100 Ankara, Turkey
  • 7. Baskent Univ, Fac Med, Dept Neurol, TR-06490 Ankara, Turkey
  • 8. Cukurova Univ, Fac Med, Dept Physiol, TR-01330 Adana, Turkey

Description

The biological basis for the development of the cerebro-cerebellar structures required for posture and gait in humans is poorly understood. We investigated a large consanguineous family from Turkey exhibiting an extremely rare phenotype associated with quadrupedal locomotion, mental retardation, and cerebro-cerebellar hypoplasia, linked to a 7.1-Mb region of homozygosity on chromosome 17p13.1-13.3. Diffusion weighted imaging and fiber tractography of the patients' brains revealed morphological abnormalities in the cerebellum and corpus callosum, in particular atrophy of superior, middle, and inferior peduncles of the cerebellum. Structural magnetic resonance imaging showed additional morphometric abnormalities in several cortical areas, including the corpus callosum, precentral gyrus, and Brodmann areas BA6, BA44, and BA45. Targeted sequencing of the entire homozygous region in three affected individuals and two obligate carriers uncovered a private missense mutation, WDR81 p.P856L, which cosegregated with the condition in the extended family. The mutation lies in a highly conserved region of WDR81, flanked by an N-terminal BEACH domain and C-terminal WD40 beta-propeller domains. WDR81 is predicted to be a transmembrane protein. It is highly expressed in the cerebellum and corpus callosum, in particular in the Purkinje cell layer of the cerebellum. WDR81 represents the third gene, after VLDLR and CA8, implicated in quadrupedal locomotion in humans.

Files

bib-7b0a48f2-900e-4b6a-b5dd-7034319a7d3d.txt

Files (395 Bytes)

Name Size Download all
md5:1fc3668cb309aea62ed236fcb31480bf
395 Bytes Preview Download