Distinguishing the four genetic causes of jouberts syndrome–related disorders

Abstract

Joubert syndrome is a severe developmental disorder mainly consisting of ataxia, oculomotor apraxia and mental retardation and characterized by cerebellar vermis hypoplasia and a peculiar brainstem malformation known as the "molar tooth sign" 1,2 . Patients frequently display additional features of cystic kidney disease progressing to renal failure and ocular manifestations including retinopathy, encompassing the Joubert Syndrome Related Disorders (JSRD) group of conditions [3][4][5] . We used homozygosity mapping to identify a novel locus on chromosome 12 and subsequently truncating mutations in the centrosomal protein 290 (CEP290) gene in four families and a missense mutation in a fifth family. These families display pleiotropic forms of JSRD with variable retinal and renal manifestations. CEP290 expression was detected in developing murine tissues, most notably in proliferating cerebellar granule neuron populations, and showed centrosome and cilia intracellular localization in non-neuronal cells. Our data imply a direct connection between JSRDs and other cilia/centrosomal human disorders such as isolated nephronophthisis, Senior-Loken, Bardet-Biedl and Meckel syndromes 6,7 . 4 Joubert syndrome (JS) is an autosomal recessive disorder presenting with psychomotor delay, hypotonia, ataxia, oculomotor apraxia and breathing abnormalities in the neonatal period 1 . Neuroradiologically, JS is characterized by a peculiar malformation of the midbrain-hindbrain junction known as the "molar tooth sign" (MTS), consisting of cerebellar vermis hypo/aplasia, thick and mal-oriented superior cerebellar peduncles and abnormally deep interpeduncular fossa 2 . The MTS has subsequently been reported in a group of syndromes termed "Joubert Syndrome Related Disorders" (JSRDs), displaying the neurological features of JS associated with involvement of other organs such as the eye and kidney (mainly retinal dystrophy and nephronophthisis). Additional clinical features include optic coloboma, polydactyly, liver fibrosis and other central nervous system malformations 3-4 . At least eight distinct syndromes sharing the MTS have been described so far. However, their nosologic delineation is still problematic due to the wide phenotypic variability both within and among families 5 . Genetic heterogeneity mirrors clinical heterogeneity of JSRDs, with two genes (AHI1/JBTS3 and NPHP1/JBTS4) and two additional genetic loci (JBTS1 and JBTS2) identified so far [8][9][10][11][12][13] . has been detected in six families characterized by multiorgan involvement and 5 striking phenotypic variability 18 . In our series, eighteen consanguineous JSRD families did not show linkage to any of the known loci, supporting further genetic heterogeneity. In the largest family (COR27), a simulation study performed with the program SLINK revealed a maximum expected LOD score of 3.60, indicating that this family was informative to detect linkage. A 10-cM resolution genome-wide screen identified a marker on chromosome 12q (D12S1064) that generated a LOD score of...

Nephronophthisis-Associated Ciliopathies

“…NPHP may be associated with tapetoretinal degeneration (Senior-Løken syndrome [SLSN] [34,35]), cerebellar vermis aplasia (Joubert syndrome [JBTS] [36,37]), ocular motor apraxia type Cogan (38), mental retardation (21,39), liver fibrosis (40), or coneshaped epiphyses of the phalanges (Mainzer-Saldino syndrome [41]). Infantile NPHP type 2 (17) can be associated with situs inversus (17), retinitis pigmentosa (42), or cardiac ventricular septal defect (17).…”

“…In JBTS, a developmental disorder with multiple organ involvement, NPHP or cystic dysplasia occurs in association with coloboma of the eye (or retinal degeneration); with aplasia/hypoplasia of the cerebellar vermis causing ataxia; and with the facultative symptoms of psychomotor retardation, polydactyly, occipital encephalocele, and episodic neonatal tachypnea/dyspnea (36,37,(47)(48)(49). A pathognomonic diagnostic feature of JBTS on axial magnetic resonance imaging of the brain is the presence of prominent superior cerebellar peduncles, termed the "molar tooth sign" of the midbrain-hindbrain junction (49,50).…”

High NPHP1 and NPHP6 Mutation Rate in Patients with Joubert Syndrome and Nephronophthisis

“…Of these, JBTS3 is the only locus with which a diseasespecific gene has been identified, AHI1 (9,10). The phenotype that is linked to JBTS1 and JBTS3 loci was initially found to be restricted to neurologic and retinal involvement (11); however, more recently, AHI1 mutations have also been detected in patients with both JS and nephronophthisis (12,13). JBTS2 was also associated with renal and hepatic abnormalities (6,7).…”

Manifestações renais na síndrome de Joubert

“…A displasia cística é caracterizada pela presença de múltiplos cistos de dimensões variáveis, visualizados em ultrassom de rins e vias urinárias e podem estar presentes desde o nascimento. O achado de displasia cística é característico da variante da síndrome de Joubert conhecida como Dekaban-Arima (24)(25)(26) . A nefronoftise juvenil é caracterizada por microcistos em túbulos renais, causando defeitos na concentração urinária.…”