Novel indel mutation in CDMP1 gene is associated with brachydactyly type C in a four generation Turkish family

Abstract

The cartilage derived morphogenetic protein-1 (CDMP1), also referred asthe growth/differentiation factor 5 (GDF5) gene, has been shown to be akey regulator in the bone morphogenic protein pathway (BMP) duringskeletal and joint development. Heterozygous loss-of-function mutationsreported to cause hypoplasia/aplasia of certain skeletal elements (brachydactyly),heterozygous gain-of-function mutations, occurring either on thegene itself or through the loss of its inhibitor noggin, result in joint fusion(symphalangism). Furthermore, homozygous mutations, predominantlyaffecting the limbs have been described; Grebe type dysplasia, Du Pan Syndrome,Acromesomelic Dysplasia-Hunter Thompson type. Also reported ishomozygous missense mutation presenting with brachydactyly, formulatingphenotype-genotype correlations by type and domain inconceivable, likelydue to the in����luence of other factors impacting the developmental pathway.Presently, 34 mutations dispersed throughout propeptide and chain domainsof CDMP1, associated with eight different OMIM entries, have beendescribed.We ascertain here two affecteds, one female and one male, with brachdactylytype C (MIM# 113100) presenting with disproportionate shortness of the2nd and 3rd ����ingers and hypersegmentation of the proximal and middle 2ndand 3rd phalanges. These cases are from a family that reports an additional8 affected members spanning across four generations. CDMP1 analysis revealeda novel heterozygous in frame indel mutation (c.803_827del25ins25)in the propeptide domain (p.cys268_ser276delCPSGRQPASinsLLSALLDVN).This is the second indel mutation ascribed to the CDMP1. The previouslypublished indel mutation was of the out-of-frame type in homozygous state,in the chain motif, associated with Du Pan Syndrome. Our novel mutationfurther emphasizes the allelic heterogeneity of CDMP1.