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Patterns of Inheritance: Mendelian and Non-Mendelian
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Merlin G. Butler, Michael Begleiter, Shannon Lillis, Molly Lund, F. John Meaney
Because females have two copies of the X chromosome and males are hemizygous, most X-linked conditions are more common in males than females. Geneticists divide X-linked conditions into two categories depending on whether the X-linked gene is dominant or recessive which is based on the affected status of the females. In X-linked recessive conditions, female carriers are usually not affected but in the X-linked dominant conditions females are consistently affected. Pedigrees for X-linked recessive genetic diseases have characteristics that are clearly distinguishable from autosomal dominant and recessive genetic diseases. These are illustrated by the pedigree in Fig. 10. Since a father can only transmit a Y chromosome to his sons, X-linked genes are not passed from father to son. Thus, male-to-male transmission is never seen in X-linked traits unlike autosomal dominant conditions. An affected father has no affected sons yet all of his daughters will be carriers of the X-linked condition. If a female carrier has a son, there is a 50% chance that he will be affected. If a female carrier has a daughter, there is a 50% that she will be a carrier. An X-linked recessive genetic disease may be passed through generations of carrier females before it is expressed in a male. Thus, affected males in a family are related through females. Lowe or oculo-cerebrorenal syndrome (Fig. 11) is an example of an X-linked recessive condition which primarily affects the eyes, central nervous system, and kidneys. Affected males have congenital cataracts and impaired vision, and almost all affected males have some degree of intellectual impairment. They also have some degree of proximal tubular renal dysfunction. Lowe syndrome is caused by markedly reduced activity of the enzyme, inositol polyphosphate 5-phosphatase (OCRL-1) which is encoded by the OCRL gene.
Hypotonia and delayed motor development as an early presentation of Lowe syndrome: case report and literature review
Published in Acta Clinica Belgica, 2019
Sara David, Kathleen De Waele, Bram De Wilde, Franny Faes, Olivier Vanakker, Sophie Walraedt, Agnieszka Prytuła
LS is a rare multisystemic disorder characterized by the triad of congenital cataract, neurological impairment and renal tubular dysfunction of variable extent. The classic presentation was first described by Lowe et al. in 1952. The molecular basis was later identified as X-linked mutations in the OCRL gene, resulting in a decreased activity of inositol polyphosphate 5-phosphatase (IPP-5P). The OCRL-1 protein has functions in the endocytic network, the actin cytoskeleton and ciliogenesis [1–3]. OCRL is highly expressed in the brain and the peripheral neural system [4,5]. At renal level, a hypothesis is that impaired trafficking of megalin results in the tubular dysfunction seen in LS [4]. A dysregulation of multiple cell processes may explain the pleiotropic phenotypic features.
Inhibitory B cell co-receptors and autoimmune diseases
Published in Immunological Medicine, 2019
B cells express various inhibitory receptors including CD22 (also known as Siglec-2), Sigle-10 (Siglec-G in mice), CD72, LILRB (PIR-B in mice), PECAM-1 (also known as CD31) and FcγRIIB (Table 1) [17,18]. These receptors contain immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic tails. Upon ligation of B cell receptor (BCR), ITIMs are phosphorylated at the tyrosine residue by the BCR-associated kinase Lyn, thereby recruiting and activating SH2-containing phosphatases such as SH2-contingin protein tyrosine phosphatase 1 (SHP-1, also known as PTPN6), SHP-2 (also known as PTPN11), and SH2 domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP1, also known as INPP5D). These phosphatases then dephosphorylate signaling molecules activated by BCR ligation, thereby negatively regulate BCR signaling. Because of the functional association with BCR, these inhibitory receptors are called inhibitory B cell co-receptors. Expression of CD22, Siglec-10/G, and CD72 is mostly restricted to B cells, whereas other inhibitory receptors are expressed in various immune cell types as well as B cells (Table 1).
Clinical characteristics of high myopia in female carriers of pathogenic RPGR mutations: a case series and review of the literature
Published in Ophthalmic Genetics, 2023
Matthew Tran, Masha Kolesnikova, Angela H. Kim, Tia Kowal, Ke Ning, Vinit B. Mahajan, Stephen H. Tsang, Yang Sun
In contrast to this trend, other authors have described pedigrees with mutations in exons 1–14 of RPGR, such as in patient 3, that are also correlated with phenotypic high myopia in female carriers (8,35,36). Particularly, Banin et al. reported a missense substitution (c.g823a, p.Gly275Ser) within exon 8 in an Israeli family, where obligate carriers suffered from high myopia, low visual acuity, restricted visual fields, and reduced ERG amplitudes (36). However, this identical variant was also identified in two Danish families, where obligate carriers had no visual complaints and normal to slightly diminished retinal function (37). Because the disease-related RPGR haplotypes in the aforementioned families were different, Banin suggested that additional genes linked to RPGR may explain the high phenotypic variability resulting from RPGR mutations and be related to the myopia observed in affected carriers (36). Exons 1–10 of RPGR encode a domain homologous to the Regulator of Chromosome Condensation 1 (RCC1), a guanine nucleotide exchange factor for Ran, consisting of seven blade-shaped beta sheets forming a beta-propeller structure (Figure 6) (12). Binding sites for proteins such as RPGR interacting protein 1 (RPGRIP1) and the delta subunit of rod cyclic GMP phosphodiesterase (PDE6δ) exist in the RCC1-like domain. The deletion (c.1100delC, p.Pro367Leufs *14) in patient 3 occurred in exon 10 of RPGR, indicating a potential role of N-terminal protein interactions in the pathogenesis of disease. Inositol polyphosphate-5-phosphatase 5E (INPP5E), a potential ciliary cargo protein that interacts with the N-terminus of RPGR, has been recently implicated in the pathogenesis of RPGR-associated ciliopathies and non-syndromic inherited retinal degenerations (38,39).