Desbuquois dysplasia type I and fetal hydrops due to novel mutations in the CANT1 gene

Abstract

We report on three hydropic fetuses of 17, 22 and 25 gestational weeks from three distinct families presenting with Desbuquois dysplasia type 1. All fetuses showed brachymelia and characteristic dysmorphic features. X-ray studies revealed d-shaped extraphalangeal bones and disease-specific prominence of the lesser trochanter, varying in severity with fetal age. Early lethal manifestation of the disorder was reflected in lung hypoplasia and in early death of similarly affected siblings in cases 1 and 2. All families were German Caucasians by descent. Sequence analysis of the CANT1 gene revealed two frameshift mutations, c.228_229insC and c.277_278delCT, in homozygous and compound heterozygous configuration, respectively, and a homozygously novel missense mutation, c.336C4A (p.D112E), located within a highly conserved region of exon 2. Haplotype analyses by high-resolution single-nucleotide polymorphism array showed that the haplotype associated with c.228_229insC may be traced to a single founder in the German population.

Case of Desbuquois dysplasia type 1: Potentially lethal skeletal dysplasia

“…Recent investigations have elucidated that both types are allelic and caused by homozygous or compound heterozygous mutations in the CANT1 gene . Until now, 28 patients have been reported with the CANT1 mutation, and 24 distinct CANT1 mutations have been reported throughout the gene; these include 11 nonsense mutations, 11 missense mutations, one large deletion in 5'UTR, and one splice site mutation . The arginine 300 substitution has been identified in 6/28 unrelated Desbuquois dysplasia type 1 patients (p.Arg300Cys [3/6], p.Arg300His [3/6]).…”

“…6 Until now, 28 patients have been reported with the CANT1 mutation, and 24 distinct CANT1 mutations have been reported throughout the gene; these include 11 nonsense mutations, 11 missense mutations, one large deletion in 5'UTR, and one splice site mutation. [6][7][8][9] The arginine 300 substitution has been identified in 6/28 unrelated Desbuquois dysplasia type 1 patients (p.Arg300Cys [3/6], p.Arg300His [3/6]). The valine 226 substitution has been identified in five patients with a Kim variant phenotype from Japan/Korea, characterized by short metacarpals and elongated phalanges.…”

Ca2+-activated Nucleotidase 1, a Novel Target Gene for the Transcriptional Repressor DREAM (Downstream Regulatory Element Antagonist Modulator), Is Involved in Protein Folding and Degradation

“…As for the results on CANT1, their interest is greatly heightened by recent findings showing that nonsense or missense mutations in its gene have been found in a number of cases of severe type 1 and 2 Desbuquois dysplasia, an autosomal recessive chondrodysplasia characterized by severe prenatal and postnatal growth retardation, joint laxity, short extremities, and progressive scoliosis (23,56,57). Inclusion bodies containing proteinaceous material within distended ER cisternae have been found in fibroblasts from patients suggesting the possibility of a role for CANT1 in the endochondral ossification pro-cess (23,(57)(58)(59).…”

IMPAD1 mutations in two Catel‐Manzke like patients

“…CANT1 (calcium-activated nucleotidase 1) mutations have been reported in Desbuquois dysplasia type 1 patients presenting with a various range of hand anomalies including extra ossification centers, abnormal thumb, finger dislocations or very short metacarpals [Huber et al, 2009;Faden et al, 2010;Furuichi et al, 2011;Laccone et al, 2011].…”