Expanding the clinical and molecular spectrum of lethal congenital contracture syndrome 8 associated with biallelic variants of ADCY6

Abstract

Arthrogryposis multiplex congenita (AMC) is defined as congenital, non‐progressive contractures in more than two joints and in multiple body areas, resulting from reduced fetal mobility. So far, more than 400 causative genes for AMC have been identified. Some isolated AMC phenotypes arise as a result of mutations in genes encoding components required for motor neuron structure, function, and myelination, as in the case of ADCY6 encoding the enzyme adenylyl cyclase type 6. ADCY6 inactivation, due to biallelic variants, have been previously associated with the lethal congenital contracture syndrome 8 (LCCS8). So far, only four LCCS8 patients, from two families, have been reported. Here, we describe a new patient affected by a severe form of AMC, harboring two novel compound heterozygous variants in ADCY6. Our findings expand the clinical and mutational spectrum of LCCS8, showing a possible correlation between the impact of the ADCY6 missense variants reported to date, predicted by molecular modeling, and the severity of the phenotype.

Adenylyl cyclase 6 plays a minor role in the mouse inner ear and retina

“…Four ADCY6 mutations have been shown to cause lethal arthrogryposis multiplex congenita in humans 24 – 26 . Two of them are homozygous missense mutations (Y992C and R1116C), and the other two are compound heterozygous missense and splice site mutations (E1003K and c.1535 + 1G > A).…”

“…Two of them are homozygous missense mutations (Y992C and R1116C), and the other two are compound heterozygous missense and splice site mutations (E1003K and c.1535 + 1G > A). Homology modeling suggests that the residues affected by these missense mutations are positioned at the interface between the AC6 C2 domain and Gαs, the interface between the AC6 C1 and C2 domains, and the interface between AC6 and its ATP substrate 24 . Therefore, these missense mutations are predicted to affect AC6 activity to synthesize cAMP, which is crucial for muscle, joint, and nervous system development.…”

“…On the other hand, AC6 has been extensively studied in cardiac myocytes, where AC6 participates in the β-adrenergic receptor signaling pathway and activates Akt kinase (also known as protein kinase B) and phospholamban phosphorylation 22 , 23 . Mutations in the ADCY6 gene were found to cause abnormal peripheral axon myelination and lethal arthrogryposis multiplex congenita in humans 24 – 26 . In the cochlea, reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence studies have detected AC6 expression in hair cells, and the AC6 expression is affected by Adgrv1 knockout 9 .…”

Expression and functions of adenylyl cyclases in the CNS

“…Together, these findings highlight important roles of ADCY6 in cardiac and renal functions. In addition, homozygous missense mutation (R1116C) in ADCY6 reduces myelination in peripheral nervous system, contributing to human axoglial diseases [ 100 ] and lethal congenital contracture syndrome [ 101 ]. ADCY6 has also been identified as a prognostic factor involved in DNA methylation-regulated immune processes in luminal-like breast cancer [ 102 ].…”