Refining the phenotypical and mutational spectrum of Taybi‐Linder syndrome

Abstract

Taybi-Linder syndrome (TALS, OMIM 210710) is a rare autosomal recessive disorder belonging to the group of microcephalic osteodysplastic primordial dwarfisms (MOPD). This syndrome is characterized by short stature, skeletal anomalies, severe microcephaly with brain malformations and facial dysmorphism, and is caused by mutations in RNU4ATAC. RNU4ATAC is transcribed into a non-coding small nuclear RNA which is a critical component of the minor spliceosome. We report here four foetuses and four unrelated patients with RNU4ATAC mutations. We provide antenatal descriptions of this rare syndrome including unusual features found in two twin foetuses with compound heterozygosity for two rare mutations who presented with mild intrauterine growth retardation and atypical dysmorphic facial features. We also carried out a literature review of the patients described up to now with RNU4ATAC mutations, affected either with TALS or Roifman syndrome, a recently described allelic disorder.

Microtubule binding of the kinesin-4 KIF7 and its regulation by autoinhibition

“…The physiological relevance of KIF21B’s ability to influence microtubule dynamics are unclear as two studies suggested that KIF21B decreases growth rates and a third study demonstrated an increase in growth rates in cells [51, 54, 59]. For KIF7, loss of KIF7 expression or point mutations in Kif7 lead to increased cilium length [23, 33–35], consistent with KIF7 functioning to destabilize microtubules. Our results are also consistent with a microtubule destabilizing function for KIF7 in cells as expression of KIF7(1-558) caused a decrease in the microtubule growth rate as measured by EB3-mCherry.…”

“…KIF7 has also been suggested to regulate the length of the primary cilium and organization of the cilium tip [33]. Indeed, humans and mice with Kif7 mutations have longer cilia [23, 33–35]. These ciliary functions of KIF7 are thought to be due to the ability of the motor to bind selectively to the plus ends of microtubules and regulate microtubule dynamics [33, 36].…”

Minor spliceosome disruption causes limb growth defects without altering patterning

“…The severity of primordial dwarfism observed in MOPD1, RS, and LWS is observed along a gradation, with MOPD1 being the most severe, RS moderate, and LWS mild 16,17 . Nonetheless, in all cases, the basic patterning of the limb skeletal elements, including the presence of a stylopod (humerus; femur), zeugopod (radius/ulna; tibia/fibula), and autopod (hand; foot), is maintained 16,17 .…”

“…For example, m icrocephalic o steodysplastic p rimordial d warfism type 1 (MOPD1), Roifman syndrome (RS), and Lowry-Wood syndrome (LWS) are linked to partial inhibition of the minor spliceosome 11,12,14,16 . Here, individuals harbor disparate mutations in RNU4ATAC , which encodes the U4atac snRNA, and display symptoms including microcephaly, micrognathia, vertebral deficits, and primordial dwarfism 16,17 . The severity of primordial dwarfism observed in MOPD1, RS, and LWS is observed along a gradation, with MOPD1 being the most severe, RS moderate, and LWS mild 16,17 .…”

“…Here, individuals harbor disparate mutations in RNU4ATAC , which encodes the U4atac snRNA, and display symptoms including microcephaly, micrognathia, vertebral deficits, and primordial dwarfism 16,17 . The severity of primordial dwarfism observed in MOPD1, RS, and LWS is observed along a gradation, with MOPD1 being the most severe, RS moderate, and LWS mild 16,17 . Nonetheless, in all cases, the basic patterning of the limb skeletal elements, including the presence of a stylopod (humerus; femur), zeugopod (radius/ulna; tibia/fibula), and autopod (hand; foot), is maintained 16,17 .…”