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. 2011 Sep 4;43(10):1026-30.
doi: 10.1038/ng.915.

Germline deletion of the miR-17∼92 cluster causes skeletal and growth defects in humans

Loïc de Pontual  1 , Evelyn Yao, Patrick Callier, Laurence Faivre, Valérie Drouin, Sandra Cariou, Arie Van Haeringen, David Geneviève, Alice Goldenberg, Myriam Oufadem, Sylvie Manouvrier, Arnold Munnich, Joana Alves Vidigal, Michel Vekemans, Stanislas Lyonnet, Alexandra Henrion-Caude, Andrea Ventura, Jeanne Amiel
Affiliations

Germline deletion of the miR-17∼92 cluster causes skeletal and growth defects in humans

Loïc de Pontual et al. Nat Genet. .

Abstract

MicroRNAs (miRNAs) are key regulators of gene expression in animals and plants. Studies in a variety of model organisms show that miRNAs modulate developmental processes. To our knowledge, the only hereditary condition known to be caused by a miRNA is a form of adult-onset non-syndromic deafness, and no miRNA mutation has yet been found to be responsible for any developmental defect in humans. Here we report the identification of germline hemizygous deletions of MIR17HG, encoding the miR-17∼92 polycistronic miRNA cluster, in individuals with microcephaly, short stature and digital abnormalities. We demonstrate that haploinsufficiency of miR-17∼92 is responsible for these developmental abnormalities by showing that mice harboring targeted deletion of the miR-17∼92 cluster phenocopy several key features of the affected humans. These findings identify a regulatory function for miR-17∼92 in growth and skeletal development and represent the first example of an miRNA gene responsible for a syndromic developmental defect in humans.

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Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Clinical features of patients with del13q31.3
Clinical features and radiographs of affected individuals from families AO39, AO70 and patient 248412 showing brachydactyly, brachymesophalangy of the 2nd and 5th fingers (better appreciated on the palmar view, arrows), hypoplastic thumbs of variable severity (asterisks) and cutaneous syndactyly of toes (arrow heads).
Figure 2
Figure 2. Mapping 13q31.3 microdeletions in FS patients
(a) Schematic illustration of the microdeletions identified in AO39 and AO70 families and Decipher patient 248412. (b) Genomic qPCR showing that the microdeletion segregates with the disease in families AO70 and AO39. (c) RT-qPCR showing reduced expression of individual microRNAs encoded by the miR-17~92 cluster in peripheral white blood cells of patients carrying 13q31.3 microdeletions (n=3) compared to healthy donors (n=4). For each miRNA, the mean relative expression and the range of expression (error bars) compared to control donors are shown.
Figure 3
Figure 3. miR-17~92Δ/+ mice display features of FS
(a) Mice hemizygous for miR-17~92 are smaller than their wild-type littermates. Wild type (empty circles) and miR-17~92Δ/+ (filled circles) mice were weighed at P0 (left panel) or at weaning (3 weeks, right panel). P-value was computed using the two-tailed t-test. (b) Alcian blue and alizarin red staining of wild-type and miR-17~92Δ/+ forelimbs from female, age-matched mice. The 5th mesophalanx (arrow) is shorter in hemizygous animals compared to wild-type mice (bar). (c) Quantification of the relative length of the 5th mesophalanx in wild-type (n=6) and miR-17~92Δ/+ (n=10) murine forelimbs. The ratio between length of the 5th mesophalanx and length of the 5th metacarpal bone is plotted. Error bars = 1 standard deviation. (d) Lateral (left) and dorsal (right) views of mouse skulls of age-matched wild-type (top) and miR-17~92Δ/+ (bottom) male mice.
Figure 4
Figure 4. Widespread skeletal defects in E18.5miR-17~92Δ/Δ embryos
(a) Skeletal staining of the left hand of E18.5 littermate embryos. Notice the absence of the 5th mesophalanx (M) in the forelimb of the miR-17~92Δ Δ embryo (P= proximal, D = distal). Also notice the delayed ossification of metacarpal bones and of proximal phalanges, and the fusion of the first row of carpal bones (red arrowhead) in the mutant embryo. (b) Lateral views of embryonic skeletons showing delayed ossification of the skull and asymmetric fusions of the first three cervical vertebrae in the KO animals (arrow). (c) Dorsal and (d) ventral views of the skulls of miR-17~92Δ/Δ and wild-type E18.5 embryos, showing microcephalia and delayed ossification of occipital, parietal and frontal bones in mutant embryos.
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