Inactivation of AMMECR1 is associated with growth, bone, and heart alterations

Abstract

We report five individuals with loss-of-function of the X-linked AMMECR1: a girl with a balanced X-autosome translocation and inactivation of the normal X-chromosome; two boys with maternally inherited and de novo nonsense variants; and two half-brothers with maternally inherited microdeletion variants. They present with short stature, cardiac and skeletal abnormalities, and hearing loss. Variants of unknown significance in AMMECR1 in four male patients from two families with partially overlapping phenotypes were previously reported. AMMECR1 is coexpressed with genes implicated in cell cycle regulation, five of which were previously associated with growth and bone alterations. Our knockdown of the zebrafish orthologous gene resulted in phenotypes reminiscent of patients' features. The increased transcript and encoded protein levels of AMMECR1L, an AMMECR1 paralog, in the t(X;9) patient's cells indicate a possible partial compensatory mechanism. AMMECR1 and AMMECR1L proteins dimerize and localize to the nucleus as suggested by their nucleic acid-binding RAGNYA folds. Our results suggest that AMMECR1 is potentially involved in cell cycle control and linked to a new syndrome with growth, bone, heart, and kidney alterations with or without elliptocytosis.

Xq22.3q23 microdeletion harboring TMEM164 and AMMECR1 genes: Two case reports confirming a recognizable phenotype with short stature, midface hypoplasia, intellectual delay, and elliptocytosis

“…Unfortunately only a picture of a patient without AMMECR1 deletion has been published (a patient from family 2 in Meloni et al, ). This patient has thick lips, contrasting with thin lips in our patients and other patients with involvement of AMMECR1 (Andreoletti et al, ; Basel‐Vanagaite et al, ; Gazou et al, ; Meloni et al, ; Moysés‐Oliveira et al, ). We find a peculiar aspect of the upper lip that is thin and tends to point in its middle part at the level of the cupid bow.…”

“…In order to further delineate the genotype–phenotype correlation, we compared our cases with other cases with Xq22.3q23 microdeletions and AMMECR1 pathogenic variants reported in the literature (Table , Figure ). Most of the main features in our patients are also found in patients with pathogenic variants (missense and nonsense pathogenic variants) in the AMMECR1 gene (Andreoletti et al, ; Basel‐Vanagaite et al, ; Moysés‐Oliveira et al, ), that is mild intellectual disability, developmental delay, hearing loss, short stature, elliptocytosis, and facial dysmorphism including midface hypoplasia and cardiac and bone features (Moysés‐Oliveira et al, ). Minor features such as fifth finger clinodactyly are also found (Table ).…”

“…AMMECR1 is known to be highly conserved throughout the evolution (Vitelli et al, ) but the function of the protein AMMECR1 yet remains unknown. AMMECR1 protein may be involved in the control of cell division (Moysés‐Oliveira et al, ).…”

“…As the precise role of AMMECR1 protein is not known, it is currently challenging to establish a link between the occurrence of the nodular lymphocyte lymphoma and AMMECR1 deletion. Interestingly though, a recent publication suggests the implication of AMMECR1 protein in mitotic cell cycle control (Moysés‐Oliveira et al, ). Further studies are therefore needed to refine a possible link.…”

“…COL4A5 point pathogenic variants and intragenic deletions or duplications are known to cause Alport syndrome (Savige, ). Recently, using exome sequencing, missense and nonsense pathogenic variants in AMMECR1 have been associated with intellectual disability, midface hypoplasia, elliptocytosis, cardiac, and bone features (Andreoletti et al, ; Basel‐Vanagaite et al, ; Moysés‐Oliveira et al, ). In these cases, hematuria and proteinuria were absent.…”