%0 Journal Article %J Am J Hum Genet %D 2015 %T Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3. %A Chong, Jessica X %A Burrage, Lindsay C %A Beck, Anita E %A Marvin, Colby T %A McMillin, Margaret J %A Shively, Kathryn M %A Harrell, Tanya M %A Buckingham, Kati J %A Bacino, Carlos A %A Jain, Mahim %A Alanay, Yasemin %A Berry, Susan A %A Carey, John C %A Gibbs, Richard A %A Lee, Brendan H %A Krakow, Deborah %A Shendure, Jay %A Nickerson, Deborah A %A Bamshad, Michael J %K Arthrogryposis %K Cytoskeletal Proteins %K Exome %K Genetic Predisposition to Disease %K High-Throughput Nucleotide Sequencing %K Humans %K Mutation %K Myosins %K Osteogenesis %X

Multiple pterygium syndrome (MPS) is a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis, and congenital contractures of the limbs. MPS typically segregates as an autosomal-recessive disorder, but rare instances of autosomal-dominant transmission have been reported. Whereas several mutations causing recessive MPS have been identified, the genetic basis of dominant MPS remains unknown. We identified four families affected by dominantly transmitted MPS characterized by pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis. Exome sequencing identified predicted protein-altering mutations in embryonic myosin heavy chain (MYH3) in three families. MYH3 mutations underlie distal arthrogryposis types 1, 2A, and 2B, but all mutations reported to date occur in the head and neck domains. In contrast, two of the mutations found to cause MPS in this study occurred in the tail domain. The phenotypic overlap among persons with MPS, coupled with physical findings distinct from other conditions caused by mutations in MYH3, suggests that the developmental mechanism underlying MPS differs from that of other conditions and/or that certain functions of embryonic myosin might be perturbed by disruption of specific residues and/or domains. Moreover, the vertebral fusions in persons with MPS, coupled with evidence of MYH3 expression in bone, suggest that embryonic myosin plays a role in skeletal development.

%B Am J Hum Genet %V 96 %P 841-9 %8 2015 May 07 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/25957469?dopt=Abstract %R 10.1016/j.ajhg.2015.04.004 %0 Journal Article %J Am J Hum Genet %D 2013 %T Mutations in KCTD1 cause scalp-ear-nipple syndrome. %A Marneros, Alexander G %A Beck, Anita E %A Turner, Emily H %A McMillin, Margaret J %A Edwards, Matthew J %A Field, Michael %A de Macena Sobreira, Nara Lygia %A Perez, Ana Beatriz A %A Fortes, Jose A R %A Lampe, Anne K %A Giovannucci Uzielli, Maria Luisa %A Gordon, Christopher T %A Plessis, Ghislaine %A Le Merrer, Martine %A Amiel, Jeanne %A Reichenberger, Ernst %A Shively, Kathryn M %A Cerrato, Felecia %A Labow, Brian I %A Tabor, Holly K %A Smith, Joshua D %A Shendure, Jay %A Nickerson, Deborah A %A Bamshad, Michael J %K Abnormalities, Multiple %K Amino Acid Sequence %K Branchio-Oto-Renal Syndrome %K Co-Repressor Proteins %K Ear, External %K Ectodermal Dysplasia %K Exome %K Female %K Humans %K Hypospadias %K Male %K Molecular Sequence Data %K Muscle Hypotonia %K Mutation, Missense %K Nipples %K Pedigree %K Phenotype %K Protein Structure, Tertiary %K Repressor Proteins %K Scalp %K Sequence Homology, Amino Acid %X

Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2α (TFAP2A) via its BTB domain, and mutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a potential overlap in the pathogenesis of SEN syndrome and BOFS. The identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.

%B Am J Hum Genet %V 92 %P 621-6 %8 2013 Apr 04 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/23541344?dopt=Abstract %R 10.1016/j.ajhg.2013.03.002