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Il gene CLCN4 codifica la proteina CIC-4, uno scambiatore 2Cl-\/H+ espresso in compartimenti intracellulari in un’ampia variet\u00e0 di tessuti, ma soprattutto nel cervello e nel muscolo scheletrico. Si ritiene che ClC-4 sia espresso all’interno delle cellule sugli endosomi e probabilmente sul reticolo endoplasmatico e che sia coinvolto nell’omeostasi ionica degli endosomi e nel traffico intracellulare. Un ruolo della CIC-4 nella differenziazione neuronale \u00e8 stato suggerito da studi sui topi: i neuroni ippocampali di topi Clcn4 knockout e di neuroni wild-type sottoposti a knockdown di Clcn4 mediato da shRNA mostrano una riduzione del numero totale di rami dendritici per neurone. Tuttavia, la fisiopatologia del disturbo CLCN4-correlato nell’uomo \u00e8 ancora incompleta.<\/p>\n
Lo spettro di mutazioni comprende varianti frameshift, missense e splice site e microdelezioni cromosomiche.
Le varianti missense patogene si raggruppano all’interno dei domini elicoidali trans o intermembrana della proteina, o del dominio della cistationina-\u03b2-sintasi (CBS), che si ritiene sia importante per il gating dell’antiporter. Tutte le varianti missenso finora conosciute che si raggruppano in queste regioni hanno dimostrato di avere un effetto funzionale sugli studi elettrofisiologici quando sono state espresse eterologicamente in oociti di Xenopus laevis. Tutte le femmine affette finora conosciute presentano una variante missenso in CLCN4: le portatrici eterozigoti in famiglie con varianti con perdita di funzione prevista hanno fenotipi essenzialmente normali.<\/p>\n
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