Co-occurrence of mutations in KIF7 and KIAA0556 in Joubert syndrome with ocular coloboma, pituitary malformation and growth hormone deficiency: a case report and literature review

Abstract

Background: Joubert syndrome is a recessive neurodevelopmental disorder characterized by clinical and genetic heterogeneity. Clinical hallmarks include hypotonia, ataxia, facial dysmorphism, abnormal eye movement, irregular breathing pattern cognitive impairment and, the molar tooth sign is the pathognomonic midbrain-hindbrain malformation on magnetic resonance imaging. The disorder is predominantly caused by biallelic mutations in more than 30 genes encoding proteins with a pivotal role in morphology and function of the primary cilium. Oligogenic inheritance or occurrence of genetic modifiers has been suggested to contribute to the variability of the clinical phenotype. We report on a family with peculiar clinical spectrum Joubert syndrome molecularly and clinically dissecting a complex phenotype, in which hypogonadism, pituitary malformation and growth hormone deficiency occur as major features. Case presentation: A 7 year-old male was enrolled in a dedicated "Undiagnosed Patients Program" for a peculiar form of Joubert syndrome complicated by iris and retinochoroidal coloboma, hypogonadism pituitary malformation, and growth hormone deficiency. The molecular basis of the complex phenotype was investigated by whole exome sequencing. The concomitant occurrence of homozygosity for mutations in KIF7 and KIAA0556 was identified, and the assessment of major clinical features associated with mutations in these two genes provided evidence that these two independent events represent the cause underlying the complexity of the present clinical phenotype. Conclusion: Beside the clinical variability of Joubert syndrome, co-occurrence of mutations in ciliopathy-associated genes may contribute to increase the clinical complexity of the trait.

ABbs5mouse model reveals pituitary cilia contributions to developmental abnormalities

“…Conditional ablation of Bbs5 at both juvenile and adult stages does not appear to result in enlarged ventricles.In summary, the Bbs5 mutant mouse described here will be a good model to evaluate multiple phenotypes associated with BBS patients. Importantly, this includes pituitary defects.Pituitary abnormalities have been reported in both BBS and Joubert Syndrome (JBTS; OMIM 213300) patients(35,39). This study is the first to show defects in pituitary development in a BBS mouse model.…”

Katnip is required to maintain microtubule function and lysosomal delivery to autophagosomes and phagosomes

“…Whilst there remain very few studies of Katnip function, it has a growing association with human disease. In addition to several studies finding Katnip mutations in patients with Joubert's syndrome (Cauley et al, 2019;Niceta et al, 2020;Sanders et al, 2015), reduced expression was also found to be associated with Alzheimer's disease (Andres-Benito et al, 2018). Heterozygous mutations in Katnip were also recently associated with hypothalamic hamartoma tumours (Fujita et al, 2019).…”

“…Viability under starvation was performed based upon (Otto et al, 2003a). Cells were washed twice, resuspended at 5 x 10 5 /mL in SIH -Arg/Lys and maintained in shaking flasks.…”

WD40-Repeat Proteins in Ciliopathies and Congenital Disorders of Endocrine System

“…The endocrine feature is also common in other ciliopathies such as JS and JSRD. Some JS/JSRD patients show growth hormone or thyroid hormone deficiency [ 127 ], CPHD [ 128 ], and micropenis [ 129 ].…”