Nature Genetics
24, 84 - 87 (2000)
doi:10.1038/71743
Molecular mechanism for duplication 17p11.2— the homologous recombination
reciprocal of the Smith-Magenis microdeletionLorraine Potocki1, 2, 6, Ken-Shiung Chen1, 6, Sung-Sup Park1, Doreen E. Osterholm1, Marjorie A. Withers1, Virginia Kimonis3, Anne M. Summers4, Wendy S. Meschino4, Kwame Anyane-Yeboa5, Catherine D. Kashork1, Lisa G. Shaffer1
& James R. Lupski1, 21
Department of Molecular and Human Genetics, Baylor
College of Medicine, Houston, Texas, USA.
2
Department of Pediatrics and Texas Children's Hospital,
Baylor College of Medicine, Houston, Texas,
USA. 3
Department of Pediatrics, Southern Illinois University,
School of Medicine, Springfield, Illinois,
USA. 4
Department of Genetics, North York General Hospital, Toronto, Canada. 5
Department of Pediatrics, Columbia University, New
York, New York, USA. 6
These authors contributed equally to this work.
Correspondence should be addressed to James R. Lupski jlupski@bcm.tmc.edu.Recombination between repeated sequences at various loci of the human genome
are known to give rise to DNA rearrangements associated with many genetic
disorders1. Perhaps the most extensively characterized genomic
region prone to rearrangement is 17p12, which is associated with the peripheral
neuropathies, hereditary neuropathy with liability to pressure palsies (HNPP)
and Charcot-Marie-Tooth disease type 1A (CMT1A;ref. 2).
Homologous recombination between 24-kb flanking repeats, termed CMT1A−REPs,
results in a 1.5-Mb deletion that is associated with HNPP, and the reciprocal
duplication product is associated with CMT1A (ref. 2).
Smith-Magenis syndrome (SMS) is a multiple congenital anomalies, mental retardation
syndrome associated with a chromosome 17 microdeletion, del(17)(p11.2p11.2)
(ref. 3,4). Most patients
(>90%) carry deletions of the same genetic markers and define a common deletion5,
6,
7. We report seven unrelated patients with de novo duplications
of the same region deleted in SMS. A unique junction fragment, of the same
apparent size, was identified in each patient by pulsed field gel electrophoresis
(PFGE). Further molecular analyses suggest that the de novo17p11.2
duplication is preferentially paternal in origin, arises from unequal crossing
over due to homologous recombination between flanking repeat gene clusters
and probably represents the reciprocal recombination product of the SMS deletion.
The clinical phenotype resulting from duplication [dup(17)(p11.2p11.2)] is
milder than that associated with deficiency of this genomic region. This mechanism
of reciprocal deletion and duplication via homologous recombination may not
only pertain to the 17p11.2 region, but may also be common to other regions
of the genome where interstitial microdeletion syndromes have been defined.
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