Search

[Purpose]: This study aimed to identify the genetic cause of a new multiple congenital anomalies syndrome observed in three individuals from two unrelated families., [Methods]: Clinical assessment was conducted prenatally and at different postnatal stages. Genetic studies included exome sequencing (ES) combined with single-nucleotide polymorphism (SNP) array based homozygosity mapping and trio ES. Dermal fibroblasts were used for functional assays., [Results]: A clinically recognizable syndrome characterized by severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet was identified. Additional features included eye abnormalities, hearing impairment, and electroencephalogram anomalies. ES detected different homozygous truncating variants in MAPKAPK5 in both families. Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization., [Conclusion]: Our data indicate that loss-of-function variants in MAPKAPK5 result in a severe developmental disorder and reveal a major role of this gene in human brain, heart, and limb development., We are grateful to patients and their parents for their participation in this study. The work at IIB was financially supported by the Spanish Ministry of Science, Innovation and Universities (PID2019-105620RB-I00/AEI/10.13039/501100011033 and SAF2016‐75434‐R (AEI/FEDER, UE).

During animal development, HOX transcription factors determine the fate of developing tissues to generate diverse organs and appendages. The power of these proteins is striking: mis-expressing a HOX protein causes homeotic transformation of one body part into another. During development, HOX proteins interpret their cellular context through protein interactions, alternative splicing, and post-translational modifications to regulate cell proliferation, cell death, cell migration, cell differentiation, and angiogenesis. Although mutation and/or mis-expression of HOX proteins during development can be lethal, changes in HOX proteins that do not pattern vital organs can result in survivable malformations. In adults, mutation and/or mis-expression of HOX proteins disrupts their gene regulatory networks, deregulating cell behaviors and leading to arthritis and cancer. On the molecular level, HOX proteins are composed of DNA binding homeodomain, and large regions of unstructured, or intrinsically disordered, protein sequence. The primary roles of HOX proteins in arthritis and cancer suggest that mutations associated with these diseases in both the structured and disordered regions of HOX proteins can have substantial functional effects. These insights lead to new questions critical for understanding and manipulating HOX function in physiological and pathological conditions.

Atelosteogenesis (AO) types I, II, and II are a group of usually lethal short-limb skeletal dysplasias. They are characterized by an abnormal, characteristic faces and hypoplastic or very shortened bones. All three forms have abnormal facies and short limbs, but associated findings, such as synpolydactyly, omphaloceles, and frontal encephaloceles, are seen in AO type I, multiple joint dislocations and abnormal hands in AO III, and increased nuchal thickness and hitchhiker thumbs in AOII help distinguish them from each other. AOI and AOIII are dominantly inherited; AOII is a recessive disorder. Neonates with all forms of AO frequently succumb usually in infancy resultant from respiratory compromise, although some individuals with AO III survive.

The HoxdDel(11-13) mutant is one of the animal models for human synpolydactyly, characterized by short and syndactylous digits. Here we have characterized in detail the cartilage and bone defects in these mutants. We report two distinct phenotypes: (i) a delay and change in pattern of chondrocyte maturation of metacarpals/metatarsals and (ii) formation of a poor and not centrally positioned primary ossification center in the proximal-intermediate phalanx. In the metacarpals of HoxdDel(11-13) mutants, ossification occurs postnataly, in the absence of significant Ihh expression and without the establishment of growth plates, following patterns similar to those of short bones. The strong downregulation in Ihh expression is associated with a corresponding increase of the repressor form of Gli3. To evaluate the contribution of this alteration to the phenotype, we generated double HoxdDel(11-13);Gli3 homozygous mutants. Intriguingly, these double mutants showed a complete rescue of the phenotype in metatarsals but only partial phenotypic rescue in metacarpals. Our results support Hox genes being required in a dose-dependent manner for long bone cartilage maturation and suggest that and excess of Gli3R mediates a significant part of the HoxdDel(11-13) chondrogenic phenotype., M.C.G-M was a recipient of JAE-Doc 2008 fellowship co-funded by FSE. This work was supported by grant BFU2011-24972 from the Spanish Ministry of Science and Innovation to M.A.R.