October 22, 2007

Mutant mice provide clues on cause of cleft
palates, other severe deformities in humans
Deficiency in a crucial gene causes gross deformities and early death
Medical specialists in a multinational project combined some old-fashioned sleuthingwith sophisticated genetic research to solve a longstanding medical mystery over whysome babies are stillborn and others are delivered with cleft palates or other severe
developmental disabilities. Reported in the online journal Nature Medicine, the research
could have far-reaching implications for the study of human developmental biology.
The study was a collaborative effort by scientists from RIKEN, led by Shiro Ikegawa, aswell as those from Tokyo Metropolitan Kiyose Children's Hospital, Tokyo Medical andDental University, Cedars-Sinai Medical Center, the David Geffen School of Medicine at
the University of California at Los Angeles, Freiburg University Hospital, University
Medical Center Utrecht, Chiba University, Japan Science and Technology Agency, andTokyo Metropolitan Institute of Medical Science.
Geneticists first stripped a gene, called solute carrier-35 D1 (SLC35D1), from speciallybred lab mice, observed the subsequent deformity of the bones and cartilage passed onto successive generations, then closely analyzed the mouse DNA for clues as to why
the deformity was occurring. They determined that SLC35D1 plays a key role in skeletal
development during prenatal growth. Mice with the gene deficiency were born withskeletal dysplasia, a lethal form of skeletal deformity with severe shortening of limbs
and facial structures. Detailed analysis of cartilage under a microscope revealed
distinctive characteristics of the cellular structure, including connective protein lattices
that were severely shortened and misshapen.
Members of the research team then located six patients with a developmental condition
known as 'Schneckenbecken dysplasia,' another severe form of skeletal dysplasia anda recessive trait that can be passed on to subsequent generations. Analysis of their
DNA identified that in all cases they too were deficient in the crucial gene.
Schneckenbecken dysplasia is a very rare genetic disorder involving defective boneand cartilage development that causes a cleft palate, short neck and short stature.

Other hallmarks include a misshapened rib cage, severe flattening of backbone
vertebra, and short, thick long bones. The condition generally results in stillbirth or deathsoon after birth.
The near-perfect match of the DNA samples - patient-to-patient as well as
patient-to-mouse - was telling evidence, the study authors believe, that they had foundthe cause not only for Schneckenbecken dysplasia but possibly for a range ofdevelopmental ailments seen in newborns. The finding could eventually lead to a'genetic fix' of irregular chromosomes in fetuses found to be expressing the trait whilestill in the womb.
As well, the use of 'mouse models' to replicate other genetic abnormalities in humans
gives medical specialists an ideal tool for first uncovering the cause, then developing
treatments to directly cure it or reduce the likelihood of it being passed down in familylines. Such an approach provides opportunities for genetic studies that cannot beperformed on human patients.
Researchers from more than a dozen facilities in Japan, the U.S., Germany and theNetherlands participated, coordinated by researchers at the Laboratory for
Developmental Genetics at the RIKEN Research Center for Allergy and Immunology inYokohama and the Laboratory of Bone and Joint Diseases at the Single Nucleotide
Polymorphism Research Center in Tokyo.
Original work:Hiraoka, S., Furuichi, T., Nishimura, G., Shibata, S., Yanagishita, M., Rimoin, D.,
Superti-Furga, A., Nikkels, P., Ogawa, M., Katsuyama, K., Toyoda, H., Kinoshita-Toyoda,A., Ishida, N., Isono, K., Sanai, Y., Cohn, D., Koseki, H. and Ikegawa., S.
Nucleotide-sugar transporter SLC35D1 is critical to chondroitin sulfate synthesis in
cartilage and skeletal development in mouse and human. Nature Medicine, published
online on Dec. 22, 2007
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