Two novel disease-causing variants in BMPR1B are associated with brachydactyly type A1

European Journal of Human Genetics : EJHG
Lemuel RacachoDennis E Bulman

Abstract

Brachydactyly type A1 is an autosomal dominant disorder primarily characterized by hypoplasia/aplasia of the middle phalanges of digits 2-5. Human and mouse genetic perturbations in the BMP-SMAD signaling pathway have been associated with many brachymesophalangies, including BDA1, as causative mutations in IHH and GDF5 have been previously identified. GDF5 interacts directly as the preferred ligand for the BMP type-1 receptor BMPR1B and is important for both chondrogenesis and digit formation. We report pathogenic variants in BMPR1B that are associated with complex BDA1. A c.975A>C (p.(Lys325Asn)) was identified in the first patient displaying absent middle phalanges and shortened distal phalanges of the toes in addition to the significant shortening of middle phalanges in digits 2, 3 and 5 of the hands. The second patient displayed a combination of brachydactyly and arachnodactyly. The sequencing of BMPR1B in this individual revealed a novel c.447-1G>A at a canonical acceptor splice site of exon 8, which is predicted to create a novel acceptor site, thus leading to a translational reading frameshift. Both mutations are most likely to act in a dominant-negative manner, similar to the effects observed in BMPR1B mutations that ca...Continue Reading

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Citations

Nov 19, 2015·European Journal of Endocrinology·Jan M WitSarina G Kant
Aug 24, 2019·Current Osteoporosis Reports·Pushpanathan Muthuirulan, Terence D Capellini
Sep 5, 2018·Nature Genetics·Lillias H MaguireElizabeth K Speliotes
Mar 28, 2018·European Journal of Human Genetics : EJHG·Yeşerin YıldırımAslıhan Tolun
Jan 25, 2021·Molecular Genetics & Genomic Medicine·Marcin BednarekAnna Wójcicka
May 16, 2019·Current Opinion in Systems Biology·Shayne D WierbowskiHaiyuan Yu
Jul 29, 2019·Cellular and Molecular Gastroenterology and Hepatology·Michael CamilleriAnne F Peery

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Methods Mentioned

BETA
transfection
Assay

Software Mentioned

ClustalOmega
Human Splice Finder
VAST
Cn3D
ExonPrimer
PolyPhen
SplicePort
SIFT
BLAT
ANTRO

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