Hyccin, the Molecule Mutated in the Leukodystrophy Hypomyelination and Congenital Cataract (HCC), Is a Neuronal Protein

Abstract

“Hypomyelination and Congenital Cataract”, HCC (MIM #610532), is an autosomal recessive disorder characterized by congenital cataract and diffuse cerebral and peripheral hypomyelination. HCC is caused by deficiency of Hyccin, a protein whose biological role has not been clarified yet. Since the identification of the cell types expressing a protein of unknown function can contribute to define the physiological context in which the molecule is explicating its function, we analyzed the pattern of Hyccin expression in the central and peripheral nervous system (CNS and PNS). Using heterozygous mice expressing the b-galactosidase (LacZ) gene under control of the Hyccin gene regulatory elements, we show that the gene is primarily expressed in neuronal cells. Indeed, Hyccin-LacZ signal was identified in CA1 hippocampal pyramidal neurons, olfactory bulb, and cortical pyramidal neurons, while it did not colocalize with oligodendroglial or astrocytic markers. In the PNS, Hyccin was detectable only in axons isolated from newborn mice. In the brain, Hyccin transcript levels were higher in early postnatal development (postnatal days 2 and 10) and then declined in adult mice. In a model of active myelinogenesis, organotypic cultures of rat Schwann cells (SC)/Dorsal Root Ganglion (DRG) sensory neurons, Hyccin was detected along the neurites, while it was absent from SC. Intriguingly, the abundance of the molecule was upregulated at postnatal days 10 and 15, in the initial steps of myelinogenesis and then declined at 30 days when the process is complete. As Hyccin is primarily expressed in neurons and its mutation leads to hypomyelination in human patients, we suggest that the protein is involved in neuron-to-glia signalling to initiate or maintain myelination.

Novel FAM126A mutations in hypomyelination and congenital cataract disease

“…Although hyccin specific mechanisms of action are still unknown, its primary expression in cells of the neuronal lineage suggests its involvement in the neuron-to-glia crosstalk which regulates the onset of myelination and/or myelin maintenance [3].…”

“…Hypomyelination and congenital cataract (HCC, OMIM #610532) is a rare autosomal recessive disorder characterized by congenital cataract, progressive neurologic impairment, and myelin deficiency in the central and peripheral nervous system [1,2]. FAM126A gene (OMIM ⁄610531; previously named DRCTNNB1A) encoding a novel neuronal protein, hyccin, is responsible for the disorder [1,3]. The phenotype ranges from a severe early-onset neurologic impairment to a relatively mild clinical picture.…”

Hipomielinização: caracterização clínica, eletrofisiológica e de neuroimagem

“…É uma doença com herança autossômica recessiva, de penetrância completa, causada por mutações no gene FAM126A (family with sequence similarity 126, member A) (72) , anteriormente identificado como DRCTNNB1A (70,71,74,75) , interação neurônio-glia para o início e manutenção da mielinização (76) .…”

“…Estas lesões correspondem a áreas de desmielinização, evoluem com atrofia e não se associam à gravidade da doença (23,72,75) . Alguns autores postulam que a presença concomitante de hipomielinização e focos de lesões desmielinizantes periventriculares seja capaz de distinguir radiologicamente a HCC das demais leucodistrofias hipomielinizantes (76) .…”

“…As alterações de neuroimagem encontradas, compatíveis com HCC (23,72,75) , foram a ausência de mielinização na substância branca hemisférica, cerebelar e do tronco encefálico em associação a lesões de desmielinização, com repercussão no FLAIR, nas adjacências dos cornos anteriores dos ventrículos laterais. A coexistência de hipomielinização e lesões desmielinizantes periventriculares foi postulada como típica de HCC, capaz de diferenciá-la de outras leucodistrofias hipomielinizantes (76) .…”