@article {340, title = {Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Jan 05}, pages = {21-30}, abstract = {

Fibromuscular dysplasia (FMD) is a heterogeneous group of non-atherosclerotic and non-inflammatory arterial diseases that primarily involves the renal and cerebrovascular arteries. Grange syndrome is an autosomal-recessive condition characterized by severe and early-onset vascular disease similar to FMD and variable penetrance of brachydactyly, syndactyly, bone fragility, and learning disabilities. Exome-sequencing analysis of DNA from three affected siblings with Grange syndrome identified compound heterozygous nonsense variants in YY1AP1, and homozygous nonsense or frameshift YY1AP1 variants were subsequently identified in additional unrelated probands with Grange syndrome. YY1AP1 encodes yin yang 1 (YY1)-associated protein 1 and is an activator of the YY1 transcription factor. We determined that YY1AP1 localizes to the nucleus and is a component of the INO80 chromatin remodeling complex, which is responsible for transcriptional regulation, DNA repair, and replication. Molecular studies revealed that loss of YY1AP1 in vascular smooth muscle cells leads to cell cycle arrest with decreased proliferation and increased levels of the cell cycle regulator p21/WAF/CDKN1A and disrupts TGF-β-driven differentiation of smooth muscle cells. Identification of YY1AP1 mutations as a cause of FMD indicates that this condition can result from underlying genetic variants that significantly alter the phenotype of vascular smooth muscle cells.

}, keywords = {Adolescent, Adult, Bone and Bones, Brachydactyly, Cell Cycle Checkpoints, Exome, Female, Fibromuscular Dysplasia, Genes, Recessive, Heterozygote, Homozygote, Humans, Learning Disorders, Male, Middle Aged, Muscle, Smooth, Vascular, Mutation, Nuclear Proteins, Pedigree, Syndactyly, Syndrome, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.11.008}, author = {Guo, Dong-Chuan and Duan, Xue-Yan and Regalado, Ellen S and Mellor-Crummey, Lauren and Kwartler, Callie S and Kim, Dong and Lieberman, Kenneth and de Vries, Bert B A and Pfundt, Rolph and Schinzel, Albert and Kotzot, Dieter and Shen, Xuetong and Yang, Min-Lee and Bamshad, Michael J and Nickerson, Deborah A and Gornik, Heather L and Ganesh, Santhi K and Braverman, Alan C and Grange, Dorothy K and Milewicz, Dianna M} } @article {422, title = {Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures".}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {815-823}, abstract = {

Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylometaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of "corner fractures" at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo~FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70~kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.

}, keywords = {Adolescent, Adult, Bone and Bones, Bone Diseases, Developmental, Cartilage, Child, Child, Preschool, Exome, Female, Fibronectins, Fractures, Bone, Humans, Male, Mutation, Osteochondrodysplasias, Phenotype, Scoliosis}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.019}, author = {Lee, Chae Syng and Fu, He and Baratang, Nissan and Rousseau, Justine and Kumra, Heena and Sutton, V Reid and Niceta, Marcello and Ciolfi, Andrea and Yamamoto, Guilherme and Bertola, D{\'e}bora and Marcelis, Carlo L and Lugtenberg, Dorien and Bartuli, Andrea and Kim, Choel and Hoover-Fong, Julie and Sobreira, Nara and Pauli, Richard and Bacino, Carlos and Krakow, Deborah and Parboosingh, Jillian and Yap, Patrick and Kariminejad, Ariana and McDonald, Marie T and Aracena, Mariana I and Lausch, Ekkehart and Unger, Sheila and Superti-Furga, Andrea and Lu, James T and Cohn, Dan H and Tartaglia, Marco and Lee, Brendan H and Reinhardt, Dieter P and Campeau, Philippe M} } @article {454, title = {P4HA1 mutations cause a unique congenital disorder of connective tissue involving tendon, bone, muscle and the eye.}, journal = {Hum Mol Genet}, volume = {26}, year = {2017}, month = {2017 06 15}, pages = {2207-2217}, abstract = {

Collagen prolyl 4-hydroxylases (C-P4Hs) play a central role in the formation and stabilization of the triple helical domain of collagens. P4HA1 encodes the catalytic α(I) subunit of the main C-P4H isoenzyme (C-P4H-I). We now report human bi-allelic P4HA1 mutations in a family with a congenital-onset disorder of connective tissue, manifesting as early-onset joint hypermobility, joint contractures, muscle weakness and bone dysplasia as well as high myopia, with evidence of clinical improvement of motor function over time in the surviving patient. Similar to P4ha1 null mice, which die prenatally, the muscle tissue from P1 and P2 was found to have reduced collagen IV immunoreactivity at the muscle basement membrane. Patients were compound heterozygous for frameshift and splice site mutations leading to reduced, but not absent, P4HA1 protein level and C-P4H activity in dermal fibroblasts compared to age-matched control samples. Differential scanning calorimetry revealed reduced thermal stability of collagen in patient-derived dermal fibroblasts versus age-matched control samples. Mutations affecting the family of C-P4Hs, and in particular C-P4H-I, should be considered in patients presenting with congenital connective tissue/myopathy overlap disorders with joint hypermobility, contractures, mild skeletal dysplasia and high myopia.

}, keywords = {Animals, Basement Membrane, Bone and Bones, Child, Collagen Type IV, Connective Tissue, Humans, Male, Mice, Mice, Knockout, Muscles, Mutation, Osteochondrodysplasias, Procollagen-Proline Dioxygenase, Prolyl Hydroxylases, Tendons}, issn = {1460-2083}, doi = {10.1093/hmg/ddx110}, author = {Zou, Yaqun and Donkervoort, Sandra and Salo, Antti M and Foley, A Reghan and Barnes, Aileen M and Hu, Ying and Makareeva, Elena and Leach, Meganne E and Mohassel, Payam and Dastgir, Jahannaz and Deardorff, Matthew A and Cohn, Ronald D and DiNonno, Wendy O and Malfait, Fransiska and Lek, Monkol and Leikin, Sergey and Marini, Joan C and Myllyharju, Johanna and B{\"o}nnemann, Carsten G} } @article {269, title = {Sclerocornea in a patient with van den Ende-Gupta syndrome homozygous for a SCARF2 microdeletion.}, journal = {Am J Med Genet A}, volume = {164A}, year = {2014}, month = {2014 May}, pages = {1170-4}, abstract = {

Van den Ende-Gupta Syndrome (VDEGS) is an autosomal recessive disorder characterized by blepharophimosis, distinctive nose, hypoplastic maxilla, and skeletal abnormalities. Using homozygosity mapping in four VDEGS patients from three consanguineous families, Anastacio et al. [Anastacio et al. (2010); Am J Hum Genet 87:553-559] identified homozygous mutations in SCARF2, located at 22q11.2. Bedeschi et al. [2010] described a VDEGS patient with sclerocornea and cataracts with compound heterozygosity for the common 22q11.2 microdeletion and a hemizygous SCARF2 mutation. Because sclerocornea had been described in DiGeorge-velo-cardio-facial syndrome but not in VDEGS, they suggested that the ocular abnormalities were caused by the 22q11.2 microdeletion. We report on a 23-year-old male who presented with bilateral sclerocornea and the VDGEGS phenotype who was subsequently found to be homozygous for a 17 bp deletion in exon 4 of SCARF2. The occurrence of bilateral sclerocornea in our patient together with that of Bedeschi et al., suggests that the full VDEGS phenotype may include sclerocornea resulting from homozygosity or compound heterozygosity for loss of function variants in SCARF2.

}, keywords = {Abnormalities, Multiple, Adult, Arachnodactyly, Blepharophimosis, Bone and Bones, Chromosomes, Human, Pair 22, Contracture, Cornea, Corneal Diseases, Exons, Facies, Hand Deformities, Congenital, Homozygote, Humans, Male, Phenotype, Radiography, Scavenger Receptors, Class F, Sequence Analysis, DNA, Sequence Deletion, Young Adult}, issn = {1552-4833}, doi = {10.1002/ajmg.a.36425}, author = {Migliavacca, Michele P and Sobreira, Nara L M and Antonialli, Graziela P M and Oliveira, Mariana M and Melaragno, Maria Isabel S A and Casteels, Ingele and de Ravel, Thomy and Brunoni, Decio and Valle, David and Perez, Ana Beatriz A} }