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      Microcephalic Osteodysplastic Primordial Dwarfism, Type II: a Clinical Review

      review-article
      1 , 2 , , 3
      Current Osteoporosis Reports
      Springer US
      MOPDII, Primordial dwarfism, Pericentrin

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          Abstract

          Purpose of the Review

          This review will provide an overview of the microcephalic primordial dwarfism (MPD) class of disorders and provide the reader comprehensive clinical review with suggested care guidelines for patients with microcephalic osteodysplastic primordial dwarfism, type II (MOPDII).

          Recent Findings

          Over the last 15 years, significant strides have been made in the diagnosis, natural history, and management of MOPDII.

          Summary

          MOPDII is the most common and well described form of MPD. The classic features of the MPD group are severe pre- and postnatal growth retardation, with marked microcephaly. In addition to these features, individuals with MOPDII have characteristic facies, skeletal dysplasia, abnormal dentition, and an increased risk for cerebrovascular disease and insulin resistance. Biallelic loss-of-function mutations in the pericentrin gene cause MOPDII, which is inherited in an autosomal recessive manner.

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          Most cited references50

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          Mutations in the pericentrin (PCNT) gene cause primordial dwarfism.

          Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin (PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism type II (MOPD II) in 25 patients. Adults with this rare inherited condition have an average height of 100 centimeters and a brain size comparable to that of a 3-month-old baby, but are of near-normal intelligence. Absence of PCNT results in disorganized mitotic spindles and missegregation of chromosomes. Mutations in related genes are known to cause primary microcephaly (MCPH1, CDK5RAP2, ASPM, and CENPJ).
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            Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I.

            Small nuclear RNAs (snRNAs) are essential factors in messenger RNA splicing. By means of homozygosity mapping and deep sequencing, we show that a gene encoding U4atac snRNA, a component of the minor U12-dependent spliceosome, is mutated in individuals with microcephalic osteodysplastic primordial dwarfism type I (MOPD I), a severe developmental disorder characterized by extreme intrauterine growth retardation and multiple organ abnormalities. Functional assays showed that mutations (30G>A, 51G>A, 55G>A, and 111G>A) associated with MOPD I cause defective U12-dependent splicing. Endogenous U12-dependent but not U2-dependent introns were found to be poorly spliced in MOPD I patient fibroblast cells. The introduction of wild-type U4atac snRNA into MOPD I cells enhanced U12-dependent splicing. These results illustrate the critical role of minor intron splicing in human development.
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              Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling.

              Large brain size is one of the defining characteristics of modern humans. Seckel syndrome (MIM 210600), a disorder of markedly reduced brain and body size, is associated with defective ATR-dependent DNA damage signaling. Only a single hypomorphic mutation of ATR has been identified in this genetically heterogeneous condition. We now report that mutations in the gene encoding pericentrin (PCNT)--resulting in the loss of pericentrin from the centrosome, where it has key functions anchoring both structural and regulatory proteins--also cause Seckel syndrome. Furthermore, we find that cells of individuals with Seckel syndrome due to mutations in PCNT (PCNT-Seckel) have defects in ATR-dependent checkpoint signaling, providing the first evidence linking a structural centrosomal protein with DNA damage signaling. These findings also suggest that other known microcephaly genes implicated in either DNA repair responses or centrosomal function may act in common developmental pathways determining human brain and body size.
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                Author and article information

                Contributors
                302 651 5916 , Michael.Bober@nemours.org
                +44 (0) 131 651 8500 , Andrew.jackson@igmm.ed.ac.uk
                Journal
                Curr Osteoporos Rep
                Curr Osteoporos Rep
                Current Osteoporosis Reports
                Springer US (New York )
                1544-1873
                1544-2241
                13 April 2017
                13 April 2017
                2017
                : 15
                : 2
                : 61-69
                Affiliations
                [1 ]ISNI 0000 0001 2166 5843, GRID grid.265008.9, Stanley Kimmel Medical College, , Thomas Jefferson University, ; Philadelphia, PA USA
                [2 ]ISNI 0000 0004 0458 9676, GRID grid.239281.3, , A. I. DuPont Hospital for Children, ; 1600 Rockland-Road, Wilmington, DE 19803 USA
                [3 ]ISNI 0000 0004 1936 7988, GRID grid.4305.2, MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, , University of Edinburgh, ; Edinburgh, EH4 2XU UK
                Article
                348
                10.1007/s11914-017-0348-1
                5561166
                28409412
                51cae81c-fb53-42c2-bc70-04250349c7a2
                © Springer Science+Business Media New York 2017
                History
                Categories
                Rare Bone Disease (C Langman and E Shore, Section Editors)
                Custom metadata
                © Springer Science+Business Media New York 2017

                Orthopedics
                mopdii,primordial dwarfism,pericentrin
                Orthopedics
                mopdii, primordial dwarfism, pericentrin

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