Trafficking defects and loss of ligand binding are the underlying causes of all reported DDR2 missense mutations found in SMED-SL patients.

Spondylo-meta-epiphyseal dysplasia (SMED) with short limbs and abnormal calcifications (SMED-SL) is a rare, autosomal recessive human growth disorder, characterized by disproportionate short stature, short limbs, short broad fingers, abnormal metaphyses and epiphyses, platyspondyly and premature calcifications. Recently, three missense mutations and one splice-site mutation in the DDR2 gene were identified as causative genetic defects for SMED-SL, but the underlying cellular and biochemical mechanisms were not explored. Here we report a novel DDR2 missense mutation, c.337G>A (p.E113K), that causes SMED-SL in two siblings in the United Arab Emirates. Another DDR2 missense mutation, c.2254C>T (p.R752C), matching one of the previously reported SMED-SL mutations, was found in a second affected family. DDR2 is a plasma membrane receptor tyrosine kinase that functions as a collagen receptor. We expressed DDR2 constructs with the identified point mutations in human cell lines and evaluated their localization and functional properties. We found that all SMED-SL missense mutants were defective in collagen-induced receptor activation and that the three previously reported mutants (p.T713I, p.I726R and p.R752C) were retained in the endoplasmic reticulum. The novel mutant (p.E113K), in contrast, trafficked normally, like wild-type DDR2, but failed to bind collagen. This finding is in agreement with our recent structural data identifying Glu113 as an important amino acid in the DDR2 ligand-binding site. Our data thus demonstrate that SMED-SL can result from at least two different loss-of-function mechanisms: namely defects in DDR2 targeting to the plasma membrane or the loss of its ligand-binding activity.

A novel mutation in ARG1 gene is responsible for arginase deficiency in an Asian family.

Argininemia is a rare autosomal recessive metabolic disorder caused by a deficiency in the arginase enzyme, which is the final enzyme in the urea cycle and responsible for the hydrolysis of arginine to urea and ornithine. The disease becomes symptomatic during childhood and is characterized by progressive spastic quadriplegia, progressive mental impairment, growth retardation, and periodic episodes of hyperammonemia. At least 19 distinct mutations in the ARG1 gene have been identified indicating the molecular heterogeneity of this condition. We report a homozygous novel mutation (c.93 delG) in the ARG1 gene from 3 affected children of a Pakistani family living in the United Arab Emirates. The mutation is expected to lead to a frame shift after the thirtieth residue and a stop codon at residue 44 (p.T30fsX14). Therefore, this mutation is expected to result in complete loss-of-function of the arginase enzyme and therefore is the mostly likely cause of argininemia in this family.