**9. Global ciliary dysfunction in pleiotropic human diseases**


136 Neuroimaging for Clinicians – Combining Research and Practice

multiple ciliary protein complexes. Disruption of these complexes due to mutations in component proteins is an underlying cause of associated photoreceptor degeneration. Here, we highlight the recent developments in understanding the mechanism of cilia-dependent photoreceptor degeneration due to mutations in RPGR and PGR-interacting proteins in severe genetic diseases, including retinitis pigmentosa, Leber congenital amaurosis (LCA), Joubert syndrome, and Senior-Loken syndrome. Additionally, we explore the physiological

relevance of photoreceptor ciliary protein complexes [88, 89].

3 Situs inversus

7 Liver disease

Badano JL, et al [74]

**Cognitive impairment** 

8 Retinitis Pigmentosa 9 Mental retardation

the tubules are significantly distorted, indicating a loss of PCP [96].

Table 2. Clinical features that may predict cilia involvement (listed by relevance) From:

RENAL: Polycystic kidney disease (PKD) [90], and Nephronophthisis [91]. PKD is the most common inherited disease in the United States. Current estimates are that 600 000 patients have PKD in the US, with 12.5 million cases worldwide (for a recent, comprehensive review on PKD see [90]. The inherited PKDs include autosomal dominant type (ADPKD), autosomal recessive (ARPKD), and nephronophthisis. ADPKD, the most common form, occurs in 1 amongst 600–800 live births and affects 500 000 persons in the US. The disease occurs during adult life and is characterized by extensive cystic enlargement of both kidneys. Of the two types of ADPKD, type I is caused by a mutation in the PKD1 gene, and type II by a mutation in the PKD2 gene [92]. The proteins encoded by both genes are transmembrane proteins. Polycystin 1 is proposed to be a cell–cell and cell– matrix adhesion receptor [93] and polycystin 2 is thought to act as a calcium-permeable membrane channel [94]. Polycystic kidney is the result of altered intraciliar transport of non-motile primary cilia of the renal tubule epithelial cells [95]. In PKD, cyst formation is associated with increased numbers of cells in the circumference of renal tubules. In mice with renal-specific inactivation of Tcf2, and in the *pck*  rat, which has reduced expression of *Pkd2* and/or *Pkhd1*, mitotic alignments along the axis of

Patients with ciliary dysfunction disorders display variably expressive brain dysgenesis as well as neurocognitive impairments. Joubert syndrome is a ciliopathy defined by cerebellar vermis hypoplasia, oculomotor apraxia, intermittent hyperventilation, and mental retardation. Recent evidence suggests important roles for the primary cilium in mediating a host of extracellular signaling events such as morphogen, mitogen, homeostatic and polarity signals. Based upon the clinical features of ciliopathies and cilia mediated signaling

1 Dandy-Walker Syndrome 2 Corpus callosum agenesis

4 Posterior Encephalocele 5 Renal cystic disease 6 Postaxial polydactyly


### **Bardet-Biedl syndrome (BBS) or Laurence Moon-Biedl syndrome [99].**

Retinal dystrophy, obesity, and polydactyly.

INHERITANCE: RA. Genes:12 BBS genes. Locus:11q13; 16q21; 3p12-q13; 15q22.3; 2q31; 20p12; 4q27; 14q32.11; 7p14; 12q; 9q33.1; 4q27.

PHENOTYPE: Obesity (83%). Polydactyly, syndactyly, or both (75%). Mental Retardation (80%), spinocerebellar degeneration. Retinal degeneration: Retinitis pigmentosa (68%) with night vision problems, loss of peripheric-central vision. By the age of 20, 73% are blind. Genital hypoplasia, hypogonadism (60%). Renal cystic disease. Other: nystagmus, anosmia, asthma, diabetes insipidus, cardiac malformations and situs inversus.

#### **Alström (Alms) Syndrome**

INHERITANCE: RA; GENE: ALMS1; Locus:2P13. Protein: Alström syndrome protein 1.

PHENOTYPE: Obesity. Type 2 diabetes mellitus. Sensorineural hearing loss (cochlear neuronal degeneration). Photophobia and nystagmus (degeneration of photoreceptor cone cells). Others: short stature, cardiomyopathy, liver and renal failure, hypogonadism.

#### **Meckel-Gruber Syndrome**

INHERITANCE: RA. Genetic heterogeneity. 3 loci: M*KS1* on 17q23, *MKS2* on 11q13, *MKS3*  on 8q21.13-q22.1

PHENOTYPE: A fatal disease, characterized by: occipital encephalocele, bilateral renal cystic dysplasia, hepatic ductal dysplasia and cysts, and polydactyly.

#### **Orofaciodigital syndrome 1**

INHERITANCE: X-linked Dominant (fatal in males). GENE: OFD1; Locus: Xp22.3-p22.2. PROTEIN: Oral-facial-digital syndrome 1 protein.

PHENOTYPE: ORAL: Membrane between oral mucosa and alveolar bone. Partial clefts: upper lip, tongue, alveolar, palate. FACIAL: alar cartilage hypoplasia, short filter, hypertelorism with lateral location of inner edges. DIGITAL: asymmetric shortening of fingers (polydactyly / syndactyly). RENAL: renal microcysts. OTHER: Mental retardation (IQ 70), agenesis of the corpus callosum, cerebellar abnormalities and hydrocephalus, alopecia ...

#### **Joubert syndrome (JBTS)**

INHERITANCE: RA. 3genes: (AHI1, NPHP1, CEP290). Incidence: 1x100.000 NB. Affects the cerebellum (vermis hypoplasia) and brainstem; appears in neonatal period with a characteristic breathing pattern of tachypnea/apnea.

Ciliopathies: Primary Cilia and Signaling Pathways in Mammalian Development 139

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PHENOTYPE: Head: macrocephaly, prominent forehead. Eyes: coloboma, nystagmus, strabismus, ptosis. Ears: low-set and thick. Nose: broad nasal bridge, epicanthus, anteverted nostrils. Open mouth, tongue protusion with rhythmic tongue movements. Neurological: generalized hypotonia, frog posture, hyperpnea followed by apnea. Ataxia. Other: polydactyly, seizures, scoliosis, congenital heart disease, pigmented retina. MRI: molar sign: There are 4 specific abnormalities: 1) Increased posterior interpeduncular fossa and decreased length of the isthmus. 2) Thick and elongated superior cerebellar peduncles in greater perpendicular orientation towards brainstem compared with normal orientation. 3) Hypoplastic or aplastic superior cerebellar vermis.4) Sagittal vermian cleft.

### **Ellis-Van Creveld syndrome**

INHERITANCE: AR. GEN: two genes (EVC y ECV2). LOCUS:14p16. Protein: EVCS protein. Condroectodermal dysplasia, Mesoectodermal dysplasia. Incidence: 0.5x100.000. 30% consanguineous. Common among the Pennsylvania Amish population.

PHENOTYPE: Acromesomelic dwarfism resulting in disproportionately short limbs, predominantly in the lower limbs and most striking distally (farthest from central trunk or midline). Final height reached is between 109 to 155cm. Postaxial polydactyly in hands and, occasionally, feet. Carpal and pastern bones fusion. Cleft lip at the junction of the upper hemi-lips, and labiogingival frenulum hypertrophy.

Congenital heart disease (50-60%), septal defects, single atrium. Differential diagnosis with short rib-polydactyly syndromes: Jeune syndrome or asphyxiating thoracic dystrophy and oro-facio-digital syndrome.

#### **Asphyxiating Thoracic Dystrophy, Jeune Syndrome.**

INHERITANCE: RA. GENES: 2 (JATD1,JATD2). LOCI :15q13, 3q24-26. Protein: intraflagellar transport protein 80 homolog

PHENOTYPE: Retinal degeneration, kidney cysts, hepatic portal fibrosis, affecting infants who die of asphyxia in the neonatal period secondary to small chest with short ribs. Skeletal: Chondrodysplasia; shortness of long bones, hypoplastic iliac wings, conical epiphysis and phalangeal fusion. Polydactyly. OTHER: impaired pancreatic ...
